Chemoselectivity and stereoselectivity of cyclisation pathways leading to bicyclic tetramates controlled by ring-chain tautomerisation in thiazolidines

Article abstract of DOI:10.1039/c6ob00557h

Chemoselective Dieckmann cyclisation reactions on N-malonyl thiazolidine templates derived from cysteine and pivaldehyde or aromatic aldehydes may be used to access bicyclic tetramates, for which different pathways operate as a result of differing ring-chain tautomeric behaviour of the respective intermediate imines.

Full text of DOI:10.1039/c6ob00557h

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Chemoselectivity and stereoselectivity of
cyclisation pathways leading to bicyclic tetramates
controlled by ring-chain tautomerisation in
thiazolidines†
Cite this: DOI: 10.1039/c6ob00557h
Tharindi D. Panduwawala, Sarosh Iqbal, Rémi Tirfoin and Mark G. Moloney*
Received 14th March 2016,
Accepted 12th April 2016
Chemoselective Dieckmann cyclisation reactions on N-malonyl thiazolidine templates derived from
cysteine and pivaldehyde or aromatic aldehydes may be used to access bicyclic tetramates, for which
different pathways operate as a result of differing ring-chain tautomeric behaviour of the respective inter-
mediate imines.
DOI: 10.1039/c6ob00557h
www.rsc.org/obc
The tetramate system occurs as a scaffold in natural products and others have found that other cyclic N,O-hemiaminal
1
,2
which exhibit a wide range of bioactivities, and we have pre- ethers derived from aldehydes and ketones are highly stable
8
–11
viously established that Dieckmann cyclisation of oxazolidine/ provided that the N-heteroatom is acylated,
aldehydes
thiazolidine templates 2a–c derived from pivaldehyde and other than pivaldehyde were unsuitable in the process shown
3
4
5
serine 1a, threonine 1b or cysteine 1c respectively may be in Scheme 1; this necessarily results in a highly hydrophobic
used to generate enantiopure tetramates 3a–c (Scheme 1). group at C-2, and limits the synthetic scope of the process.
Although this key cyclisation is highly chemo-, diastereo- and However, thiazolidine substrates derived from cysteine using
enantioselective, it has been limited to the use of pivaldehyde aromatic aldehydes were found to give hemiaminal thioether
as the initial condensing species, since this both gives rela- systems that were more stable than their oxazolidine counter-
tively stable oxazolidine/thiazolidine intermediates 2a–c and parts, and Dieckmann cyclisation successfully gave the corres-
1
2
makes for a system in which the bulky t-butyl group exerts ponding tetramate products; of interest is that ring chain
strong steric influence in a ring-chain tautomeric equilibrium tautomerism in such N,S-hemiaminal thioethers has been
5
8,13
which strongly favours the ring form. We examined the Dieck- only rarely reported.
We had assumed that this would result
mann cyclisation process in detail, and found that ring closure in a directly analogous chemo- and stereo-selective outcome to
occurred from the predominantly formed cis-acyloxazolidines that observed for the oxazolidine series, but a detailed investi-
2
a,b, in which closure from the C-5 enolate onto the ethyl ester gation has shown that this is not the case, and the results are
giving 3a–c is preferred (Scheme 1, Route a), placing the C-2 reported here.
t-butyl group on the exo-face (that is, less hindered convex face)
3
,6
of the newly generated bicyclic ring system; this is a cyclic
example of the Self Regeneration of Stereocentres concept
developed extensively by Seebach. An alternative mode of
Results and discussion
7
cyclisation, starting from the trans-acyloxazolidines 4a,b Condensation of L-cysteine methyl ester hydrochloride with the
which arise only as a very minor intermediate by epimerisa- relevant substituted benzaldehyde 6a–g gave the corres-
(
tion at C-5 under the basic conditions of the cyclisation reac- ponding stable thiazolidines 7a–g in good yield (76–94%,
tion) by closure of the more stabilised malonamide side chain Table 1) as a mixture of cis- and trans-diastereomers (readily
enolate onto the C-5 ester (Scheme 1, Route b), and also assigned by NOE (Fig. 1, ESI†)) in a ratio of between 1 : 1 and
placing the C-2 t-Bu group on the exo-face, generates the 2 : 1 (Scheme 2), and which could be readily distinguished by
alternative tetramates 5a,b as minor products. Although we difference in the chemical shift of H-2, with the value of H-2
for the trans-isomer invariably being more downfield than that
of the cis-isomer. These thiazolidines could then be converted
by DCC coupling to the corresponding malonamides 8a–g in
good yield (85–99%, Table 2), and in which the cis- to trans-
ratio (readily assigned again by NOE, (Fig. 2, ESI†)) was essen-
tially preserved from the starting thiazolidines 7a–g in all
Department of Chemistry, Chemistry Research Laboratory, The University of Oxford,
14
12 Mansfield Road, Oxford, OX1 3TA, UK. E-mail: mark.moloney@chem.ox.ac.uk
†
Electronic supplementary information (ESI) available. CCDC 1452987. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c6ob00557h
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Scheme 1
Table 1 Yields and NMR data for thiazolidines 7a–g
δ
H
(ppm) for H-2
Compound no.
cis
trans
cis : trans ratio
Yield (%)
91
7
7
7
7
7
a
b
c
5.57
5.82
1.7 : 1
5.49
5.53
5.69
5.89
5.76
5.79
5.87
6.02
1.3 : 1
1.7 : 1
0.8 : 1
0.8 : 1
94
90
94
76
d
e
7
7
f
5.43
5.48
5.71
5.68
1.2 : 1
0.9 : 1
78
85
g
cases. This is very different behaviour to the corresponding as a rotameric pair (Table 2): for the major rotamers, with the
oxazolidine series, in which the free equilibration led to a pre- exception of furfuryl 8g, H-2 for the trans-isomer was invariably
3
,6
ferred formation of the cis-malonyloxazolidine.
Again, more downfield than that of the cis-isomer, but interestingly
characteristic values of the H-2 thiazolidine chemical shifts this was reversed for the minor rotamer. Because the cis- :
were seen for each of the diastereomers, which also appeared trans-ratio is essentially unchanged in this reaction, the cis-
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Scheme 2
malonamide 8 derives from cis-thiazolidine 7 and trans-malo- bicyclic ring system. NOE analysis clearly indicated that the
namide 8 from trans-thiazolidine 7; i.e. there is no cross-over products were either 9a–g or ent-9a–g (Fig. 3, ESI†). Neither of
arising from epimerisation in the course of the acylation reac- the epimers 10 or ent-10 were formed. Mass spectrometric ana-
tion. Moreover, the cis- and trans-diastereomeric ratios of any lysis showed the formation of some tetramate 11e, but this was
recovered starting thiazolidines 7b,c,e from this reaction were only isolated from the cyclisation of cis-8e in <1% yield, indi-
the same as that of the corresponding starting thiazolidines cating that it is not the predominant product of cyclisation of
7
b,c,e used for the reaction, which further confirms that there thiazolidine-derived tetramate systems, and neither was 12
is no inter-conversion between cis- and trans-thiazolidines, or formed (which would arise by the alternative cyclisation
selective reaction, during the course of the acylation. Unfortu- pathway). This favoured pathway for the thiazolidine system
nately, the cis- and trans-diastereomers 8a–g could not be corresponds to Route b (Scheme 1) and is in contrast to the
3
,6,14
easily separated, and so the subsequent Dieckmann cyclisation t-butyl series,
and for which this mode of closure of the
step was performed on this mixture. This behaviour contrasts malonate enolate onto the C-5 methyl ester had only been a
with the corresponding t-butyl system, in which the cis-isomer minor pathway (Scheme 1, Route b). Thus, in the case of oxa-
3
2
a–c (Scheme 1) was formed predominantly.
zolidines and thiazolidines derived from the pivaldehyde
Upon reaction of malonamides 8a–g with potassium t-buto- (which therefore possess the bulky t-butyl group), ring closure
xide, ring closure was found to be very efficient (Scheme 2 by Route a proceeds preferentially since the bulky group ends
and Table 3) giving tetramate products in good yield, and up on the less hindered exo-bicyclic face, even though reaction
again with characteristic H-2 chemical shift values for the is via a relatively unfavourable enolate formation. In the case
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Table 2 Yields and NMR data for N-acylthiazolidines 8a–g
Compound
no.
δ
H
(ppm) for H-2
cis : trans
ratio
Yield
(%)
cis
trans
Major
rotamer
Minor
rotamer
Major
rotamer
Minor rotamer
6.24
8
8
8
8
8
a
b
c
6.10
6.11
6.13
6.22
6.34
6.28
6.27
6.30
6.27
6.46
6.14
6.14
6.17
6.23
6.42
1.6 : 1
1.3 : 1
1.5 : 1
0.9 : 1
0.8 : 1
99
99
87
85
97
6.24
6.29
6.24
6.45
d
e
8
8
f
6.06
6.18
6.16
6.56
6.11
6.16
6.13
1.4 : 1
0.8 : 1
81
89
g
6.32–6.35 (obscured by
H4′)
of the aryl-substituted thiazolidines 8, reaction may proceed arising from Dieckmann cyclisation, the racemic analogue of
readily by cyclisation of the malonamide enolate (Scheme 1, 9c was synthesised and this was compared with product 9c
Route b), since the smaller aryl substituent does not invoke obtained from the enantiopure series by chiral HPLC, and
the same steric demands as the t-butyl system in the bicyclic gave an ee value of 80% (Fig. 1 and 2 in the ESI†). Similarly,
product.
the ee values for 9b, 9e and 9g obtained from the corres-
However, this reduction in steric demand of the C-2 group ponding diastereomeric mixture were in the range of 76–83%.
results in an unforeseen and subtle change of selectivity in the In the case of 8f, the unseparated cis-/trans- mixture of
process. Since cyclisation was performed on the cis-/trans-dia- N-malonylthiazolidines was cyclized, and although this
stereomeric mixture of 8a–g, this leads to the additional com- successfully gave the tetramate product 9f, it was clearly of
plication that the Dieckmann ring closure might occur after compromised enantiopurity, at the least on the basis of optical
epimerisation at C-5 of cis-malonamides 8a–g under the basic rotation values.
conditions of the cyclisation reaction, while trans-malona-
mides 8a–g cyclise directly, leading to formation of either of cis- and trans-malonamide diastereomers of 8e were success-
a–g or ent-9a–g. This dual pathway does not arise to the same fully separated by careful column chromatography (other malo-
In order to study the reason for the observed ee values, the
9
extent in the case of the t-butyl system, since such epimerisa- namides could not be similarly separated). The relative
tion would lead to the much less stable trans-oxazolidine/thia- stereochemistry of each isolated malonamide diastereomer
3
,6
zolidine. Importantly, if the cyclisation and epimerisation was further confirmed by NOE (Fig. 2, ESI†), and for trans-8e,
1
5
processes were simultaneous, erosion of the ee of the product by single crystal X-ray analysis (Fig. 1). Each of these was
from the Dieckmann cyclisation reaction would result. Thus, then cyclised separately under the standard reaction con-
in order to determine the enantiomeric excess of the product ditions; trans-8e gave product 9e in 58% yield while cis-8e gave
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Table 3 Yields and NMR data for tetramates 9a–f
indicating that they are enantiomers (Fig. 3 and 4, ESI†) and
the [α] values were nearly equal in magnitude but opposite in
D
Compound no.
R
δ
H
(ppm) for H-2
% Yield
43
sign (ent-9e = +309.5 and 9e = −331.8). Thus, it is clear that
under the standard experimental conditions, trans-diastereo-
mer 8e cyclises efficiently while cis-8e does not, with the yield
ratio being close to 10 : 1. Since an ee of 83% corresponds to
an enantiomeric ratio of 10.7 : 1 and because the cyclisation of
trans-diastereomer gives approximately 10 times more yield
than cis-, the observed ee attrition could be accounted for. To
further support the difference in yields obtained for the cycli-
sation of cis- and trans-malonamides, unreacted malonamides
from the Dieckmann cyclisation step for compounds 8b, 8c
and 8e were recovered from the reaction mixture, but these
showed the presence of cis-, but no trans-, diastereomer. This
further confirms that trans-malonamides cyclise in preference
to the cis-malonamide 8, and this is in stark contrast to the
observed reactivity in the t-butyl series, in which the cis-2 pre-
ferentially closes (Scheme 1, Route a).
9
9
9
9
9
a
b
c
6.25
6.43
6.34
6.43
6.45
45
50
52
49
d
e
a
9f
6.22
6.30
78
An overall scheme of reaction is given in Scheme 3; for-
mation of the intermediate of thiazolidines 7 is favoured by
8
,16–18
ring-chain tautomerisation
of the imine derived from
9g
40
cysteine and the starting aldehyde, and the acylation of thiazo-
lidines cis-7 and trans-7 gave products cis-8 and trans-8 in
approximately equal ratios; that this a mixture of the two poss-
ibly reflects the known preference of thiazolidines to exist in
a
Isolation without acidification and extraction.
8
the ring-closed rather than the chain form. The trans-8 malo-
namides close preferentially via enolate D over the cis-8 malo-
namides, giving the product 9, but do not react to give the
alternative tetramate 11 or 12 (or their enantiomers) via
enolate B or E. However, epimerisation at C-5 under the basic
conditions of the Dieckmann cyclisation of cis-8 gives malona-
mide ent-trans-8, which can then cyclise to give the bicyclic
tetramate ent-9 via enolate C (that is, the enantiomer of that
obtained from the direct cyclisation of trans-8), but this is also
not a favoured pathway. Closure of enolates A and B to give 10
or ent-12 is not observed. In our initial report, we had assigned
ent-9 as the major product, resulting from the formation of cis-
8
as the major diastereomer (as mixture of two rotamers),
which was assigned by analogy to the similar earlier outcome
1
2
in the t-butyl series, but this is clearly in error.
Another issue of note relates to the purification of tetra-
mates 9a–g. Previously it has been reported that 3-acyltetramic
acids form metal chelates during column chromatography on
silica gel containing trace amounts of metal impurities such
2
+
2+
2+ 19–24
as Mg , Fe and Ca .
Indeed, tetramates 9d and 9e
which were purified in this way gave broad signal resonances
1
in the H NMR spectra for compounds, consistent with chela-
Fig. 1 Single crystal X-ray stucture for trans-8e.
tion. Thus, tetramates were routinely purified on silica gel
column, run with 1% Et
3
N in the eluent, and the purified
product was washed with 5% citric acid to remove any Et N
3
product ent-9e but only in 6% yield. This latter process was present to obtain the metal-free form. Moreover, it was
presumably less efficient as a result of the unfavourable initial observed that tetramates purified by preparative thin layer
epimerization of cis-8e to ent-trans-8e before closure to ent-9e chromatography with silica also resulted in NMR spectra with
is possible. NOE data clearly indicated that both products 9e peaks slightly broader than their metal-free form and with sig-
and ent-9e have the same relative stereochemistry (Fig. 3, nificant chemical shift differences observed for H-2 and H-5
ESI†). They showed different retention times on chiral HPLC (Table 4). Further, metal-chelated tetramates had different
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Scheme 3
3
Table 4 Chemical shift values of H-2 and H-5 for metal-chelated tetramates and their metal-free form (in CD OD, 400 MHz)
H
δ (ppm) Metal-free
tetramate
δ
H
(ppm) Metal-chelated tetramate
Compound no.
H-2
H-5
H-2
H-5
9d
6.43 (s)
4.13–4.32 (m)
6.32 (s)
4.95 (dd)
(
−)-9e
+)-9e
6.52 (s)
6.52 (s)
4.42 (app br. t)
4.43 (app br. t)
6.39 (s)
6.39 (s)
5.05 (dd)
5.06 (dd)
(
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2 4
physical properties in comparison to their metal free forms, extracts were washed with brine, dried over Na SO , filtered
with melting points >250 °C along with different optical and concentrated in vacuo. The residue was purified by flash
rotation data and retention times on chiral HPLC (SI). Mass column chromatography (with 1% Et N) to give the desired
spectrometric analysis of 9b showed the presence of peaks that product. The product was then dissolved in CH Cl and
could be attributable to [M − H] + Ca and [M − H] + Mg , washed with 5% citric acid. The organic fractions were dried
confirming the possibility of these tetramates chelating to over Na SO , filtered and concentrated in vacuo to yield the
desired bicyclic tetramates 9a–g.
3
2
2
2
+
2
2
4
such divalent metal cations (Figure on last page of ESI†).
In conclusion, the formation of aryl thiazolidines derived
from cysteine is readily possible, even though the corres-
(
2RS,5R)-5-Methoxycarbonyl-2-phenyl-1,3-thiazolidine 7a
ponding oxazolidines derived from serine are unstable, and Yield (2.37 g, 91%); colourless oil; inseparable 1.7 : 1 cis and
−
1
selective Dieckmann ring cyclisation gives the corresponding trans diastereomers; R = 0.48 (EtOAc : petrol; 1 : 3); νmax/cm
f
tetramate products by a highly chemoselective process, and (neat) 1736 (s, CvO), 3314 (m, N–H), δ
H 3
(400 MHz, CDCl )
with good enantioselectivity, but which proceeds in a different major isomer (cis): 2.71 (1H, br. s., NH), 3.12 (1H, dd, J = 10.3,
direction to that of the t-butyl series. These systems are 9.1 Hz, H4 ), 3.47 (1H, dd, J = 10.3, 7.1 Hz, H4 ), 3.80 (3H, s,
A
B
structurally well-defined, and offer interesting opportunities CO
2 3
CH ), 3.99 (1H, app t, J = 7.9 Hz, H5), 5.57 (1H, s, H2),
as three dimensional templates for application in drug 7.27–7.41 (3H, m, H3′, H4′), 7.52–7.56 (2H, m, H2′); minor
discovery.
isomer (trans): 2.71 (1H, br. s., NH), 3.20 (1H, dd, J = 10.5, 5.9
Hz, H4 ), 3.38 (1H, dd, J = 10.5, 7.1 Hz, H4 ), 3.78 (3H, s,
CO CH ), 4.22 (1H, app t, J = 6.4 Hz, H5), 5.82 (1H, s, H2),
7.27–7.41 (3H, m, H3′, H4′), 7.47–7.51 (2H, m, H2′);
(100.6 MHz, CDCl ) major isomer (cis): 39.2 (C4), 52.6
CO CH ), 64.3 (C5), 70.9 (C2), 127.5 (C2′), 128.5 (C3′), 128.7
C4′), 138.2 (C8), 171.6 (CO CH ); minor isomer (trans): 38.2
A
B
2
3
Experimental
δ
C
3
Synthesis of tetramic acids were carried out according to pub-
lished procedures.
(
2
3
3
,7,14
2
3
(
(
(
C4), 52.6 (CO
2 3
CH ), 65.6 (C5), 72.6 (C2), 127.0 (C2′), 127.9
General procedure 1: esterification of DL-cysteine for racemic
tetramates
+
C3′), 128.7 (C4′), 141.2 (C1′), 172.2 (CO
2
CH
3
); m/z (ESI ) 224
+
+
+
[M + H] , 100%); HRMS (ESI ); C H NNaO S [M + Na] ;
1
1
13
2
To a solution of DL-cysteine (1.0 eq.) in MeOH at 0 °C, SOCl
2
found 246.0563, requires 246.0559.
(1.2 eq.) was added dropwise and the solution warmed to rt,
(
1
2RS,5R)-2-(4-Bromophenyl)-5-methoxycarbonyl-
,3-thiazolidine 7b
then refluxed for 3 h. The reaction mixture was concentrated
in vacuo to obtain DL-cysteine methyl ester hydrochloride.
Yield (5.60 g, 94%); colourless oil; inseparable 1.3 : 1 cis and
General procedure 2: synthesis of thiazolidine
−
1
trans diastereomers; R = 0. 23 (EtOAc : petrol; 1 : 4); νmax/cm
f
3
Et N (1.2 eq.) and aldehyde (1.2 eq.) were added to L-cysteine
(
neat) 1737 (s, CvO), 3313 (m, N–H); δ
H 3
(400 MHz, CDCl )
methyl ester hydrochloride (1.0 eq.) in petrol. The mixture was
heated at reflux, with continuous removal of water using Dean
major isomer (cis): 2.64 (1H, br. s., NH), 3.10 (1H, dd, J = 10.3,
8
.8 Hz, H4 ), 3.45 (1H, dd, J = 10.5, 7.1 Hz, H4 ), 3.79 (3H, s,
A
B
2
Stark apparatus, for 19 h, then filtered and washed with Et O.
2 3
CO CH ), 3.97 (1H, dd, J = 9.1, 7.1 Hz, H5), 5.49 (1H, s, H2),
The combined filtrates were concentrated in vacuo and residue
was purified by flash column chromatography to give the
required thiazolidines 7a–g.
7
.32–7.51 (4H, m, H2′ and H3′); minor isomer (trans): 2.64 (1H,
br. s., NH), 3.15 (1H, dd, J = 10.8, 6.1 Hz, H4 ), 3.36 (1H, dd,
J = 10.5, 7.1 Hz, H4 ), 3.78 (3H, s, CO CH ), 4.13 (1H, apparent
B 2 3
A
t, J = 6.5 Hz, H5), 5.76 (1H, s, H2), 7.32–7.51 (4H, m, H2′ and
H3′); δ (100.6 MHz, CDCl ): major isomer (cis): 39.0 (C4), 52.5
General procedure 3: acylation
C
3
A solution of ethyl hydrogen malonate (1.2 eq.) in CH
2 2
2 3
Cl was (CO CH ), 65.3 (C5), 71.6 (C2), 122.4 (C1′), 129.0 (C2′), 131.6
added to a stirred solution of thiazolidine (1.0 eq.), DCC (1.2 (C3′), 137.0 (C4′), 171.3 (CO CH ); minor isomer (trans): 37.9
2
3
eq.) and DMAP (0.1 eq.) in CH Cl at 0 °C. The mixture was (C4), 52.4 (CO CH ), 64.0 (C5), 69.8 (C2), 121.5 (C1′), 128.5
2
2
2
3
+
stirred at 0 °C for 15 min and then at rt for 15 h. The reaction (C2′), 131.0 (C3′), 140.5 (C4′), 171.9 (CO CH ); m/z (ESI ) 302
2
3
+
+
+
mixture was filtered to remove dicyclohexyl urea and the ([M + H] 100%) and 304 ([M + H] 100%); HRMS (ESI );
residue was washed with CH Cl . The combined filtrates were C H O NBrS [M + H] ; found 301.98412 and 303.98175,
+
2
2
11 13 2
concentrated in vacuo and purified by flash column chromato- requires 301.98449, 303.98244.
graphy to give N-acylated thiazolidines 8a–g.
(
2RS,5R)-2-(4-Fluorophenyl)-5-methoxycarbonyl-
General procedure 4: Dieckmann cyclisation
1,3-thiazolidine 7c
t
KO Bu (1.2 eq.) was added to a solution of the N-acylated thia- Yield (2.54 g, 90%); colourless oil; inseparable 1.7 : 1 cis and
−
1
zolidine in THF and heated at reflux for 3 h. It was then cooled trans diastereomers; R = 0.35 (EtOAc : petrol; 1 : 3); νmax/cm
f
to rt, concentrated in vacuo and partitioned between Et
water. The aqueous layer was extracted and acidified with 2 M
HCl (to pH 1) and extracted with EtOAc. The combined EtOAc 3.12 (1H, dd, J = 10.3, 8.8 Hz, H4 ), 3.47 (1H, dd, J = 10.3, 7.1
2
O and (neat) 1225 (s, C–F), 1741 (s, CvO), 3311 (m, N–H);
δ
H
(400 MHz, CDCl ) major isomer (cis): 2.66 (1H, br. s., NH),
3
A
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Hz, H4
B
), 3.81 (3H, s, CO
2
CH
3
), 3.98 (1H, dd, J = 8.8, 7.1 Hz, C5′), 117.1 (d, J = 24.6 Hz, C3′), 129.7 (d, J = 8.7 Hz, C6′), 131.9
H5), 5.53 (1H, s, H2), 6.98–7.09 (2H, m, H3′), 7.49–7.54 (2H, m, (d, J = 4.0 Hz, C1′), 134.5 (d, J = 10.3 Hz, C2′), 162.1 (d, J = 252
+
+
H2′); minor isomer (trans): 2.66 (1H, br. s., NH), 3.17–3.23 (1H, Hz, C4′), 171.4 (CO
2
CH
3
); m/z (ESI ) 276 ([M + H] 100%);
+
+
m, H4
1H, app t, J = 6.5 Hz, H5), 5.79 (1H, s, H2), 6.98–7.09 (2H, m, requires 298.0075.
H3′), 7.44–7.49 (2H, m, H2′); δ (100.6 MHz, CDCl ) major
isomer (cis): 39.2 (C4), 52.6 (CO CH ), 65.4 (C5), 71.8 (C2),
15.5 (d, J = 21.5 Hz, C3′), 129.3 (d, J = 8.7 Hz, C2′), 133.9 (d,
J = 3.2 Hz, C1′), 162.8 (d, J = 247 Hz, C4′), 171.5 (CO CH ); Yield (78%); 1.2 : 1 inseparable cis and trans diastereomers;
minor isomer (trans): 38.0 (C4), 52.6 (CO CH ), 64.1 (C5), 69.9
C2), 115.1 (d, J = 21.5 Hz, C3′), 128.7 (d, J = 8.0 Hz, C2′), 136.9 (CvO), 3313 (NH); δH (400 MHz, CDCl ) major isomer (cis):
A
), 3.36–3.42 (1H, m, H4
B
), 3.80 (3H, s, CO
2
CH
3
), 4.18 HRMS (ESI ); C11
H
11ClFNNaO S [M + Na] ; found 298.0062,
2
(
C
3
(
2RS,5R)-2-(3-Bromophenyl)-5-methoxycarbonyl-
,3-thiazolidine 7f
2
3
1
1
2
3
−
1
2
3
f
R = 0.56 (EtOAc : petrol; 4 : 6), νmax/cm (neat) 1235 (C–O), 1737
(
(
3
d, J = 3.2 Hz, C1′), 162.3 (d, J = 247 Hz, C4′), 172.1 (CO
2
CH
3
); 2.55 (1H, br. s., NH), 3.04 (1H, dd, J = 10.3, 9.1 Hz, H4
A
), 3.39
+
+
+
m/z (ESI ) 264 ([M + Na] , 56%); HRMS (ESI ); C11
H
12FNNaO
2
S
(1H, dd, J = 10.3, 7.1 Hz, H4 ), 3.74 (3H, s, CO CH ), 3.91 (1H,
B
2
3
+
[M + Na] ; found 264.0460, requires 264.0465.
dd, J = 9.1, 7.1 Hz, H5), 5.43 (1H, s, H2), 7.15–7.19 (1H, m,
H5′), 7.36–7.42 (2H, m, H4′,6′), 7.62 (1H, app t, J = 1.8 Hz, H2′);
minor isomer (trans): 2.84 (1H, br. s., NH), 3.09 (1H, dd, J =
(2RS,5R)-5-Methoxycarbonyl-2-(4-nitrophenyl)-1,3-thiazolidine
7
d
1
0.5, 6.1 Hz, H4 ), 3.31 (1H, dd, J = 10.5, 7.1 Hz, H4 ), 3.73
A
B
Yield (2.95 g, 94%); yellow oil; 0.8 : 1 inseparable cis and trans (3H, s, CO
2
CH
3
), 4.07 (1H, app t, J = 6.5 Hz, H5), 5.71 (1H, s,
−
1
diastereomers; R
f
= 0.20 (EtOAc : petrol; 1 : 3); νmax/cm (neat) H2), 7.09–7.15 (1H, m, H5′), 7.30–7.34 (2H, m, H4′,6′), 7.59
1
348 (s, ArNO ), 1516 (s, ArNO ), 1730 (s, CvO), 3316 (m, N– (1H, app t, J = 1.7 Hz, H2′); δC (100.6 MHz, CDCl ) major
2
2
3
H); δ
H
(400 MHz, CDCl
3
) major isomer (trans): 2.88 (1H, br. s., isomer (cis): 39.1 (C4), 52.6 (CO
2
CH
3
), 65.4 (C5), 71.6 (C2),
A
NH), 3.08–3.16 (1H, m, H4 ), 3.36 (1H, dd, J = 10.6, 6.7 Hz, 122.4 (Ar–C), 126.2, 129.8, 130.5, 131.7 (Ar–CH), 140.5 (Ar–C),
H4 ), 3.78 (3H, s, CO CH ), 4.07 (1H, app t, J = 6.7 Hz, H5), 171.3 (CO CH ); minor isomer (trans): 38.0 (C4), 52.6
B
2
3
2
3
5
8
3
3
.87 (1H, s, H2), 7.61 (2H, d, J = 8.8 Hz, H2′), 8.12 (2H, d, J = (CO
.8 Hz, H3′); minor isomer (cis): 2.88 (1H, br. s., NH), 130.1, 130.8 (Ar–CH), 144.0 (Ar–C), 172.0 (CO
2 3
CH ), 64.1 (C5), 69.7 (C2), 122.6 (Ar–C), 125.7, 129.9,
+
2
3
CH ); m/z (ESI )
+
+
+
.08–3.16 (1H, m, H4 ), 3.46 (1H, dd, J = 10.4, 7.0 Hz, H4 ), 302 ([M + H] ); HRMS (ESI ); C H BrNNaO S [M + Na] ;
A
B
11 12
2
2 3
.78 (3H, s, CO CH ), 4.00 (1H, dd, J = 8.8, 7.0 Hz, H5), 5.59 found 323.9651, requires 323.9664.
(
1H, s, H2), 7.67 (2H, d, J = 8.8 Hz, H2′), 8.18 (2H, d, J = 8.8 Hz,
(
2RS,5R)-2-(2-Furyl)-5-methoxycarbonyl-1,3-thiazolidine 7g
H3′); δC (100.6 MHz, CDCl ): major isomer (trans): 38.1 (C4),
3
5
1
3
2.6 (CO
45.5 (C1′), 149.5 (C4′), 171.7 (CO
9.0 (C4), 52.6 (CO CH ), 65.3 (C5), 70.9 (C2), 123.7 (C3′), 128.4 1736 (s, CvO), 3317 (m, N–H); δH (400 MHz, CDCl ) major
2 3
CH ), 64.1 (C5), 69.0 (C2), 123.5 (C3′), 127.5 (C2′), Yield (3.17 g, 85%); yellow oil; 0.9 : 1 inseparable cis and trans
−
1
2
3 f
CH ); minor isomer (cis): diastereomers; R = 0.53 (EtOAc : petrol; 1 : 4); νmax/cm (neat)
2
3
3
+
(
(
C2′), 147.1 (C4′), 147.7 (C1′), 171.2 (CO
[M + H] , 100%); HRMS (ESI ); C11
2
CH
3
); m/z (ESI ) 269 isomer (trans): 2.90 (1H, br. s., NH), 2.91–2.97 (1H, m, H4
A
),
), 4.09 (1H, app t,
J = 6.7 Hz, H5), 5.68 (1H, s, H2), 6.15–6.17 (1H, m, H4′),
.18–6.20 (1H, m, H3′), 7.24–7.26 (1H, m, H5′); minor
isomer (cis): 2.90 (1H, br. s., NH), 2.91–2.97 (1H, m, H4 ),
.23–3.29 (1H, m, H4 ), 3.63 (3H, s, CO CH ), 3.81 (1H, dd, J =
+
+
+
H
12
N
2
NaO S [M + Na] ; 3.23–3.29 (1H, m, H4 ), 3.62 (3H, s, CO CH
4 B 2 3
found 291.0405, requires 291.0410.
6
(
1
2RS,5R)-2-(2-Chloro-4-fluorophenyl)-5-methoxycarbonyl-
,3-thiazolidine 7e
Yield (2.45 g, 76%); colourless oil; 0.8 : 1 inseparable cis and 9.3, 6.9 Hz, H5), 5.48 (1H, s, H2), 6.20–6.22 (1H, m, H4′),
A
3
B
2
3
= 0.58 (EtOAc : petrol; 1 : 3); νmax/cm−
1
trans diastereomers; R
f
C
6.28–6.29 (1H, m, H3′), 7.29–7.31 (1H, m, H5′); δ (100.6 MHz,
(
neat) 1226 (s, C–F), 1737 (s, CvO), 3321 (m, N–H); CDCl ): major isomer (trans): 37.9 (C4), 51.9 (CO CH ), 63.2
3
2
3
δ
H
(400 MHz, CDCl
3
) major isomer (trans): 2.65 (1H, br. s., (C2), 63.6 (C5), 106.6 (C3′), 109.6 (C4′), 141.9 (C5′), 153.2 (C2′),
), 3.33 (1H, dd, J = 10.6, 6.5 Hz, 171.1 (CO CH ); minor isomer (cis): 37.3 (C4), 51.9 (CO CH ),
H4 ), 3.81 (3H, s, CO CH ), 4.21 (1H, app t, J = 6.6 Hz, H5), 63.9 (C2), 64.8 (C5), 107.4 (C3′), 109.9 (C4′), 142.2 (C5′),
NH), 3.04–3.14 (1H, m, H4
A
2
3
2
3
B
2
3
+
+
6
7
.02 (1H, s, H2), 6.96 (2H, app td, J = 8.3, 2.5 Hz, H5′), 150.1 (C2′), 170.5 (CO
.08–7.16 (2H, m, H3′), 7.57 (2H, dd, J = 8.7, 6.1 Hz, H6′); HRMS (ESI ); C
2
CH
3
); m/z (ESI ) 214 ([M + H] 100%);
+
+
9
H
11NNaO S [M + Na] ; found 236.0351,
3
minor isomer (cis): 2.65 (1H, br. s., NH), 3.04–3.14 (1H, m, requires 236.0352.
H4 ), 3.46 (1H, dd, J = 10.4, 7.0 Hz, H4 ), 3.80 (3H, s, CO CH ),
.00 (1H, dd, J = 9.1, 6.9 Hz, H5), 5.89 (1H, s, H2), 7.03 (2H,
app td, J = 8.3, 2.6 Hz, H5′), 7.08–7.16 (2H, m, H3′), 7.74 (2H,
dd, J = 8.7, 6.1 Hz, H6′); δ (100.6 MHz, CDCl ): major isomer Yield (2.54 g, 99%); colourless oil; 1.6 : 1 inseparable cis and
trans): 37.3 (C4), 52.6 (CO CH ), 64.7 (C5), 66.5 (C2), 113.8 (d, trans diastereomers; R
A
B
2
3
(
2
2RS,5R)-1-(3-Ethoxy-3-oxopropanoyl)-5-methoxycarbonyl-
-phenyl-1,3-thiazolidine 8a
4
C
3
−
1
(
2
3
f
= 0.61 (EtOAc : petrol; 1 : 1); νmax/cm
J = 20.7 Hz, C5′), 117.0 (d, J = 24.6 Hz, C3′), 127.8 (d, J = 8.7 Hz, (neat) 1658 (s, CvO), 1734 (s, CvO); δH (400 MHz, CDCl3)
C6′), 133.5 (d, J = 10.3 Hz, C2′), 136.1 (d, J = 4.0 Hz, C1′), 161.6 major isomer (cis, a mixture of conformers): 1.09–1.21 (3H, m,
(
(
2 3 2 3 A B A B
d, J = 250 Hz, C4′), 171.9 (CO CH ); minor isomer (cis): 38.8 OCH CH ), 2.98–3.55 (4H, m, H4 , H4 , H2″ , H2″ ), 3.73 and
C4), 52.6 (CO CH ), 65.3 (C5), 67.6 (C2), 114.5 (d, J = 21.5 Hz, 3.74 (3H, s, CO CH ), 3.94–4.06 and 4.07–4.14 (2H, m,
2
3
2
3
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Paper
OCH
2 3
CH ), 4.95–5.01 (1H, m, H5), 6.10 and 6.28 (1H, s, H2), (2RS,5R)-1-(3-Ethoxy-3-oxopropanoyl)-2-(4-fluorophenyl)-5-
7
.13–7.34 (3H, m, H3′, H4′), 7.45 (2H, d, J = 7.3 Hz, H2′, minor methoxycarbonyl-1,3-thiazolidine 8c
conformer), 7.60 (2H, d, J = 7.6 Hz, H2′, major conformer),
.57–7.63 (2H, m, H2′); minor isomer (trans, a mixture of con-
Yield (2.32 g, 87%); colourless oil; 1.5 : 1 inseparable cis and
7
−1
trans diastereomers; R = 0.61 (EtOAc : petrol; 1 : 1); νmax/cm
f
formers): 1.09–1.21 (3H, m, OCH CH ), 2.98–3.55 (4H, m, H4 ,
2
3
A
(
δ
neat) 1224 (s, C–F), 1662 (s, CvO), 1741 (s, CvO);
(400 MHz, CDCl ) major isomer (cis, a mixture of conformers):
.19–1.31 (3H, m, OCH CH ), 3.07–3.55 (4H, m, H4 , H4 ,
H4
B
, H2″
A
, H2″
B
), 3.69 and 3.70 (3H, s, CO
CH
1H, m, H5), 6.14 and 6.24 (1H, s, H2), 7.13–7.34 (5H, m, H2′,
2
CH
3
), 3.94–4.06
H
3
and 4.07–4.14 (2H, m, OCH
(
2
3
), 5.16–5.19 and 5.21–5.25
1
2
3
A
B
H2″
OCH
.95–7.01 and 7.04–7.10 (2H, m, H3′), 7.48–7.54 and 7.64–7.69
2H, m, H2′); minor isomer (trans, a mixture of conformers):
.19–1.31 (3H, m, OCH CH ), 3.07–3.55 (4H, m, H4 , H4 ,
A
B 2 3
, H2″ ), 3.81 and 3.83 (3H, s, CO CH ), 4.05–4.24 (2H, m,
H3′ and H4′); δ
mixture of conformers): 13.5 and 13.6 (OCH
3
C
(100.6 MHz, CDCl
3
) major isomer (cis, a
CH ), 31.5 and
2.5 (C4), 42.6 and 42.8 (C2″), 52.2 and 52.5 (CO CH ), 60.9
2
CH ), 5.03–5.08 (1H, m, H5), 6.13 and 6.30 (1H, s, H2),
3
2
3
6
(
2
3
and 61.1 (OCH
1
1
2
CH
26.0 and 126.5 (C2′), 127.4, 128.0 (C4′), 127.7, 128.5 (C3′),
38.5 and 139.5 (C1′), 164.8 and 165.1 (C1″), 166.2 and 166.6
CH ); minor isomer (trans, a
mixture of conformers): 13.5 and 13.7 (OCH CH ), 30.5 and
3.3 (C4), 41.8 and 42.4 (C2″), 52.2 and 52.9 (CO CH ), 60.8
3
), 64.2 and 63.3 (C5), 65.7 and 66.5 (C2),
1
2
3
A
B
H2″ , H2″ ), 3.78 and 3.84 (3H, s, CO CH ), 4.05–4.24 (2H, m,
A
B
2
3
OCH
1H, s, H2), 6.95–7.01 and 7.04–7.10 (2H, m, H3′), 7.19–7.23
and 7.24–7.29 (2H, m, H2′); δC (100.6 MHz, CDCl ) major
2 3
CH ), 5.17–5.21 and 5.28–5.31 (1H, m, H5), 6.17 and 6.29
(C3″), 169.7 and 169.8 (CO
2
3
(
2
3
3
3
2
3
isomer (cis,
a
mixture of conformers): 13.9 and 14.0
and 61.1 (OCH
1
1
2
CH
24.3 and 124.5 (C2′), 127.0, 127.9 (C4′), 128.0, 128.7 (C3′),
41.5 and 141.8 (C1′), 164.2 and 164.8 (C1″), 165.8 and 166.7
3
), 63.5 and 63.83 (C5), 64.5 and 65.1 (C2),
(
OCH CH ), 32.0 and 33.8 (C4), 42.1 and 43.0 (C2″), 52.8 and
2
3
5
6
2
3.1 (CO CH ), 61.6 and 61.8 (OCH CH ), 63.7 and 64.6 (C5),
2 3 2 3
5.7 and 66.4 (C2), 115.0 (d, J = 21.5 Hz, C3′) and 115.9 (d, J =
1.5 Hz, C3′), 128.4 (d, J = 8.0 Hz, C2′) and 129.0 (d, J = 8.7 Hz,
+
+
(C3″), 169.0 and 169.8 (CO
2
CH
3
); m/z (ESI ) 338 ([M + H] ,
+
+
1
00%,), 360.0 ([M + Na] , 55%); HRMS (ESI ); C16H19NNaO S
5
C2′), 135.6 (d, J = 2.4 Hz, C1′), 162.6 (d, J = 249 Hz, C4′), 165.4
C1″), 166.6 (C3″), 170.2 (CO CH ); minor isomer (trans, a
mixture of conformers): 13.9 and 14.0 (OCH CH ), 30.9 and
+
[M + Na] ; found 360.0873, requires 360.0876.
(
2
3
2
3
3
3.0 (C4), 42.3 and 43.3 (C2″), 52.8 and 53.4 (CO CH ), 61.5
2 3
(
2RS,5R)-2-Bromophenyl-1-(3-ethoxy-3-oxopropanoyl)-5-
2 3
and 61.8 (OCH CH ), 64.0 and 64.2 (C5), 64.4 and 65.1 (C2),
1
methoxycarbonyl-1,3-thiazolidine 8b
15.3 (d, J = 22.3 Hz, C3′) and 116.2 (d, J = 21.5 Hz, C3′), 126.5
Yield (2.06 g, 99%); colourless oil; 1.3 : 1 inseparable cis and
trans diastereomers; R = 0.17 (EtOAc : petrol; 1 : 3); νmax/cm
(
d, J = 8.7 Hz, C2′) and 126.7 (d, J = 8.0 Hz, C2′), 137.9 (d, J =
−
1
f
2
1
.4 Hz, C1′), 162.5 (d, J = 248 Hz, C4′), 165.3 (C1″), 166.2 (C3″),
(neat) 1660 (s, CvO), 1738 (s, CvO); δ
H
(400 MHz, CDCl
3
)
+
+
69.3 (CO CH ); m/z (ESI ) 378 ([M + Na] , 100%); HRMS
2
3
major isomer (cis, a mixture of conformers): 1.19–1.31 (3H, m,
OCH CH ), 3.07–3.55 (4H, m, H4 , H4 , H2″ , H2″ ), 3.81 and
3
+
+
(
ESI ); C H FNNaO S [M + Na] ; found 378.0779, requires
16 18 5
2
3
A
B
A
B
378.0782.
2 3 2 3
.83 (3H, s, CO CH ), 4.03–4.24 (2H, m, OCH CH ), 5.04 (1H,
app t, J = 7.0 Hz, H5), 6.11 and 6.27 (1H, s, H2), 7.39–7.45 (2H,
m, H2′), 7.48–7.59 (2H, m, H3′); minor isomer (trans, a mixture
of conformers): 1.19–1.31 (3H, m, OCH CH ), 3.07–3.55 (4H,
2 3
(
(
2RS,5R)-1-(3-Ethoxy-3-oxopropanoyl)-5-methoxycarbonyl-2-
4-nitrophenyl)-1,3-thiazolidine 8d
m, H4
A
, H4
B
, H2″
A
, H2″
B
2 3
), 3.78 and 3.84 (3H, s, CO CH ), Yield (2.21 g, 85%); orange oil; 0.9 : 1 inseparable cis and trans
−
1
4
.03–4.24 (2H, m, OCH CH ), 5.15–5.21 and 5.26–5.33 (1H, m, diastereomers; R = 0.48 (EtOAc: petrol; 1 : 1); νmax/cm (neat)
2
3
f
H5), 6.14 and 6.24 (1H, s, H2), 7.11 (2H, d, J = 8.6 Hz, H2′ 1347 (s, ArNO
major conformer) and 7.16 (2H, d, J = 8.3 Hz, H2′ minor con- CvO); δ
former), 7.39–7.45 (2H, m, H3′) and 7.48–7.59 (2H, m, H3′); conformers); 1.07–1.21 (3H, m, OCH CH ), 2.98–3.54 (4H, m,
2
), 1520 (s, ArNO
2
), 1663 (s, CvO), 1740 (s,
H
3
(400 MHz, CDCl ): major isomer (trans, mixture of
2
3
δ
C
(100.6 MHz, CDCl
3
) major isomer (cis, a mixture of confor- H4
CH ), 32.0 and 33.9 (C4), 42.0 and 3.93–4.15 (2H, m, OCH
2.9 (C2″), 52.7 and 53.1 (CO CH ), 60.3 and 61.6 (OCH CH ), H5), 6.23 and 6.24 (1H, s, H2), 7.37–7.43 (2H, m, H2′), 8.05
A
, H4
B
, H2″
A
, H2″
B
), 3.69 and 3.76 (3H, s, CO
2 3
CH ),
mers): 13.9 and 14.1 (OCH
2
3
2
CH ), 5.20–5.22 and 5.24–5.28 (1H, m,
3
4
6
1
2
3
2
3
3.7 and 64.6 (C5), 65.6 and 66.5 (C2), 121.9 and 122.6 (C1′), (2H, app d, J = 8.8 Hz, H3′ major conformer) and 8.14 (2H, app
28.2 and 128.8 (C2′), 131.3 and 132.0 (C3′), 137.7 and 138.9 d, J = 8.6 Hz, H3′ minor conformer); minor isomer (cis,
(C4′), 165.0 and 165.3 (C1″), 166.5 and 166.9 (C3″), 170.0 and mixture of conformers); 1.07–1.21 (3H, m, OCH CH ),
2 3
1
71.0 (CO
2
CH
3
); minor isomer (trans, a mixture of confor- 2.98–3.54 (4H, m, H4
CH ), 31.0 and 33.0 (C4), 42.3 and CO CH ), 3.93–4.15 (2H, m, OCH
3.2 (C2″), 52.8 and 53.4 (CO CH ), 61.5 and 61.8 (OCH CH ), 5.05–5.09 (1H, m, H5), 6.22 and 6.27 (1H, s, H2), 7.64 (2H, d,
A
, H4
B
, H2″
A
, H2″
B
), 3.74 and 3.76 (3H, s,
mers): 13.9 and 14.0 (OCH
2
3
2
3
2
CH ), 4.89–4.95 and
3
4
6
1
2
3
2
3
4.0 and 64.2 (C5), 64.4 and 65.1 (C2), 121.3 and 122.4 (C1′), J = 8.8 Hz, H2′ minor conformer) and 7.85 (2H, d, J = 8.6 Hz,
26.5 and 126.6 (C2′), 131.6 and 132.3 (C3′), 140.9 and 141.1 H2′ major conformer), 8.05 (2H, app d, J = 8.8 Hz, H3′ minor
(
1
C4′), 164.6 and 165.2 (C1″), 166.1 and 167.2 (C3″), 169.2 and conformer) and 8.14 (2H, app d, J = 8.6 Hz, H3′ major confor-
+
+
70.0 (CO
2
CH
3
); m/z (ESI ) 416 ([M + H] 100%) and 418 ([M + mer); δ
C
(100.6 MHz, CDCl
NBrS [M + H] ; found conformers): 13.6 and 13.7 (OCH
16.01454 and 418.01234, requires 416.01618 and 418.01414. 41.9 and 42.6 (C2″), 53.0 and 53.2 (CO CH ), 61.2 and 61.5
3
) major isomer (trans, a mixture of
+
+
+
H] 100%); HRMS (ESI ); C16
4
H
19
O
5
2
CH ), 30.7 and 32.7 (C4),
3
2
3
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Organic & Biomolecular Chemistry
(OCH
2
CH
3
), 63.7 and 64.0 (C5), 63.7 and 64.3 (C2), 123.5 and dd, J = 8.7, 6.0 Hz, H6′ minor conformer), 8.24 (1H, dd, J = 8.7,
1
24.1 (C3′), 125.4 and 125.7 (C2′), 146.6 and 147.2 (C4′), 148.7 6.0 Hz, H6′ major conformer); δC (100.6 MHz, CDCl ): 13.8
3
and 149.3 (C1′), 164.9 (C1″), 165.7 and 166.9 (C3″), 168.8 and (OCH
2
CH
); minor isomer (cis, a mixture of conformers): 53.1 (CO CH
3.6 and 13.7 (OCH CH ), 31.9 and 33.9 (C4), 41.6 and 42.4 65.0 (C5), 114.1 (d, J = 21.5 Hz, C5′) and 114.5 (d, J = 20.7 Hz,
3
), 31.0 and 33.6 (C4), 41.6 and 42.6 (C2″), 52.6 and
1
1
69.6 (CO
2
CH
3
2
3
), 61.5 (OCH CH ), 62.7 and 64.3 (C2), 64.0 and
2
3
2
3
2 3 2 3
(C2″), 52.5 and 53.3 (CO CH ), 61.3 and 61.4 (OCH CH ), 63.6 C5′), 116.5 (d, J = 24.6 Hz, C3′) and 117.2 (d, J = 25.4 Hz, C3′),
and 64.5 (C5), 64.9 and 66.1 (C2), 123.2 and 123.7 (C3′), 127.2 128.2 (d, J = 8.7 Hz, C6′) and 128.8 (d, J = 8.7 Hz, C6′), 132.5 (d,
and 127.5 (C2′), 146.2 and 146.6 (C1′), 147.0 and 147.3 (C4′), J = 11.1 Hz, C2′), 133.6 (d, J = 3.2 Hz, C1′), 161.5 (d, J = 249 Hz,
1
65.1 and 165.2 (C1″), 166.1 and 166.5 (C3″), 169.8 and 170.7 C4′) and 162.0 (d, J = 251 Hz, C4′), 165.0 and 165.1 (C1″), 166.1
+
+
+
+
(
CO
2
CH
3
); m/z (ESI ) 383 ([M + H] , 100%) and 405 ([M + Na] , and 166.6 (C3″), 170.2 and 170.3 (CO
2
CH
3
); m/z (ESI ) 390 ([M
+
+
+
+
+
6
4
3%); HRMS (ESI ); C H N NaO S [M
05.0717, requires 405.0727.
+
Na] ; found
+
H] 100%), 412.0 ([M
17ClFNNaO [M
+
Na] 75%); HRMS (ESI );
1
6
18
2
7
+
C
16
H
5
S
+
Na] ; found 412.0391, requires
412.0392.
(
(
−)-(2S,5R)- and (+)-(2R,5R)-2-(2-chloro-4-fluorophenyl)-1-
3-ethoxy-3-oxopropanoyl)-5-methoxycarbonyl-1,3-thiazolidine 8e (−)-(2S,5R)- and (+)-(2R,5R)-1-(3-ethoxy-3-oxopropanoyl)-2-
(
3-bromophenyl)-5-methoxycarbonyl-1,3-thiazolidine 8f
Yield (3.06 g, 97%); 0.8 : 1 separable cis and trans diastereo-
mers; major isomer (trans, a mixture of conformers): white Yield (81%); 1.4 : 1 inseparable cis and trans diastereomers;
−
1
crystalline solid, mp 32–34 °C; R
f
= 0.16 (EtOAc : petrol; 1 : 3);
R
f
= 0.52 (EtOAc : petrol; 4 : 6), vmax/cm (neat) 1165 (C–O), 1662
); νmax/cm (neat) 1223 (s, C–F), (CvO), 1743 (CvO), 2981, 2954 (CH ); δ (400 MHz, CDCl
662 (s, CvO), 1739 (s, CvO); δH (400 MHz, CDCl ) 1.21 (3H, major isomer (cis, a mixture of conformers): 1.04–1.21 (3H, m,
2
5
−1
[α]
D
= −258.0 (c = 1.02, CHCl
3
2
H
3
)
1
3
t, J = 7.2 Hz, OCH
2
CH
3
major conformer), 1.29 (3H, t, J = 7.2 OCH
2
CH
3
), 2.98–3.55 (4H, m, H4
A
, H4
B
, H2″
A
, H2″
CH
B
), 3.66 and
), 4.91 (1H,
Hz, OCH CH minor conformer), 3.04–3.52 (4H, m, H4
2
3
A
, H4 3.71 (3H, s, CO
B
,
2
CH ), 3.92–4.15 (2H, m, OCH
3
2
3
H2″ , H2″ ), 3.79 (3H, s, CO CH major conformer), 3.85 (3H, app t, J = 7.0 Hz, H5, major rotamer), 4.98–5.01 (1H, m, H5,
A
B
2
3
s, OCH
3
minor conformer), 4.08 (2H, q, J = 7.2 Hz, OCH
CH minor confor- H2, minor rotamer), 7.03–7.79 (4H, m, Ar–CH); minor isomer
mer), 5.19–5.23 (1H, m, H5 minor conformer), 5.28–5.33 (1H, (trans, a mixture of conformers): 1.04–1.21 (3H, m, OCH CH ),
2
CH
3
minor rotamer), 6.06 (1H, s, H2, major rotamer), 6.16 (1H, s,
major conformer), 4.16–4.26 (2H, m, OCH
2
3
2
3
m, H5 major conformer), 6.42 (1H, s, H2 major conformer), 2.98–3.55 (4H, m, H4
A
, H4
B
, H2″
A
B
, H2″ ), 3.66 and 3.71 (3H, s,
6
.45 (1H, s, H2 minor conformer), 6.92 (1H, app td, J = 8.3, 2.4 CO CH ), 3.92–4.15 (2H, m, OCH
2
3
2
CH ), 5.15 (1H, d, J = 5.4 Hz,
3
Hz, H5′ minor conformer), 7.02 (1H, app td, J = 8.2, 2.4 Hz, H5, minor rotamer), 5.18–5.21 (1H, m, H5, major rotamer),
H5′ major conformer), 7.10–7.18 (2H, m, H3′ minor conformer, 6.11 (1H, s, H2, major rotamer), 6.13 (1H, s, H2, minor
H6′ major conformer), 7.20 (1H, dd, J = 8.2, 2.6 Hz, H3′ major rotamer), 7.03–7.79 (4H, m, Ar–CH); δ
C 3
(100.6 MHz, CDCl )
conformer), 7.32 (1H, dd, J = 8.7, 6.0 Hz, H6′ minor confor- 14.02, 14.13, 14.18 (OCH CH major, minor and rotamers),
2
3
mer); δ
and 32.4 (C4), 42.0 and 43.0 (C2″), 52.8 and 53.5 (CO
1.5 and 61.8 (OCH CH ), 62.0 and 62.9 (C2), 64.2 and 64.5 52.74, 53.15, 53.43, 53.77 (CO CH major, minor and rota-
C
(100.6 MHz, CDCl
3
): 13.9 and 14.0 (OCH
2
CH
3
), 30.5 31.00, 31.98, 32.99, 33.95 (C4 major, minor and rotamers),
2
CH ), 42.04, 42.27, 42.83, 43.23 (C2″ major, minor and rotamers),
3
6
2
3
2
3
(
1
(
1
C5), 113.7 (d, J = 21.5 Hz, C5′) and 114.5 (d, J = 21.5 Hz, C5′), mers), 61.41, 61.54, 61.63, 61.70 (OCH
17.4 (d, J = 25.4 Hz, C3′) and 118.0 (d, J = 24.6 Hz, C3′), 125.7 rotamers), 63.82, 63.92, 64.23, 64.70 (C5 major, minor and
d, J = 8.7 Hz, C6′) and 126.4 (d, J = 8.7 Hz, C6′), 132.5 (d, J = rotamers), 64.23, 64.70, 65.39, 66.28 (C2 major, minor and
0.3 Hz, C2′), 134.6 (d, J = 3.2 Hz, C1′) and 134.7 (d, J = 3.2 Hz, rotamers), 122.13, 122.51, 122.84, 123.13 (C3′, major, minor
C1′), 161.6 (d, J = 249 Hz, C4′) and 162.1 (d, J = 252 Hz, C4′), and rotamers), 123.76, 125.21, 125.86, 127.69, 128.00, 129.52,
64.5 and 165.0 (C1″), 165.9 and 167.4 (C3″), 169.1 and 170.0 129.89, 130.15, 130.49, 130.56, 130.81, 130.87, 131.46, 131.51
2 3
CH major, minor and
1
(
7
4
+
+
+
CO
2
CH
6%); HRMS (ESI ); C16
12.0390, requires 412.0392.
3
); m/z (ESI ) 390 ([M + H] 100%), 412.0 ([M + Na]
(C2′, C4′, C5′, C6′ major, minor and rotamers), 141.47, 142.57,
+
+
H
17ClFNNaO
5
S [M + Na] ; found 144.36, 144.70 (C1′ major, minor and rotamers), 164.91,
165.21, 165.28, 165.47 (C1″ major, minor and rotamers),
Minor isomer (cis, a mixture of conformers): colourless oil; 166.15, 166.53, 166.93, 167.00 (C3″ major, minor and rota-
2
5
R
f
= 0.24 (EtOAc : petrol; 1 : 3); [α]
D
= +124.4 (c = 1.0, CHCl
3
); mers), 169.27, 170.06, 170.10 (CO
2
CH
+
3
major, minor and rota-
H] ); HRMS (ESI );
−
1
+
+
+
νmax/cm (neat) 1226 (s, C–F), 1666 (s, CvO), 1742 (s, CvO); mers); m/z (ESI ) 416 ([M
+
minor isomer (mixture of conformers): 1.16–1.25 (3H, m,
OCH CH ), 3.03–3.51 (4H, m, H4 , H4 , H2″ , H2″ ), 3.80 (3H, 437.9981.
s, CO CH major conformer), 3.84 (3H, s, CO CH minor con-
CH ), 4.86 (1H, dd, J = 9.4, 6.2
2 3
Hz, H5 major conformer), 5.04 (1H, app t, J = 5.1 Hz,
16 5
C H18BrNNaO S [M + Na] ; found 437.9972, requires
2
3
A
B
A
B
2
3
2
3
(−)-(2S,5R)- and (+)-(2R,5R)-1-(3-ethoxy-3-oxopropanoyl)-2-
former), 4.04–4.17 (2H, m, OCH
(
2-furanyl)-5-methoxycarbonyl-1,3-thiazolidine 8g
H5 minor conformer), 6.34 (1H, s, H2 major conformer), 6.46 Yield (4.05 g, 89%); 0.8 : 1 separable cis and trans diastereo-
(
1H, s, H2 minor conformer), 6.91 (1H, app td, J = 8.4, 2.6 Hz, mers; major isomer (trans, a mixture of conformers): yellow
2
5
f D
H5′ minor conformer), 7.03 (1H, app td, J = 8.3, 2.6 Hz, H5′ solid, mp 64–66 °C; R = 0.23 (EtOAc : petrol; 1 : 2); [α] =
major conformer), 7.12 (1H, dd, J = 8.2, 2.6 Hz, H3′), 7.79 (1H, −271.7 (c = 0.23, CHCl ); νmax/cm (neat) 1664 (s, CvO), 1735
−
1
3
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Paper
(s, CvO); δ
H
(400 MHz, CDCl
3
) 1.23–1.29 (3H, m, OCH
2
CH
3
), Hz, H5), 6.25 (1H, s, H2), 7.17–7.22 (1H, m, H4′), 7.23–7.28
3
.23 (1H, app d, J = 12.5 Hz, H4 /H4 major conformer), 3.31 (2H, m, H3′), 7.35–7.41 (2H, m, H2′); δC (100.6 MHz, CDCl3):
A B
(
1H, d, J = 15.5 Hz, H2″
A
/H2″
B
major conformer), 3.38–3.40 14.1 (OCH
2 3 2 3
CH ), 32.5 (C4), 61.6 (OCH CH ), 62.2 (C2), 65.2
(
2H, m, H2″ , H2″ minor conformer), 3.45–3.49 (2H, m, H4 /
A
B
A
(C5), 98.8 (C7), 126.4 (C2′), 128.0 (C4′), 128.5 (C3′), 139.9 (C1′),
−
−
H4 minor conformer, H2″ /H2″ major conformer), 3.58 (1H, 166.9 (C9), 168.8 (C8), 185.8 (C6); m/z (ESI ) 304 ([M − H] ,
dd, J = 12.3, 6.9 Hz, H4
B
A
B
−
−
A
/H4
B
major conformer), 3.69 (1H, dd, 100%); HRMS (ESI ); C15
4
H14NO S [M − H] ; found 304.0639,
J = 12.0, 6.0 Hz, H4 /H4 minor conformer), 3.77 (3H, s, requires 304.0649.
A B
CO CH major conformer), 3.83 (3H, s, CO CH minor confor-
2
3
2
3
2 3
mer), 4.12–4.21 (2H, m, OCH CH ), 5.05 (1H, app d, J = 5.9 Hz, (−)-(2S,5R)-1-Aza-2-bromophenyl-7-ethoxycarbonyl-6-hydroxy-8-
H5 minor conformer), 5.18 (1H, app d, J = 6.8 Hz, H5 major oxo-3-thiabicyclo[3.3.0]oct-6-ene 9b
conformer), 6.16 (1H, s, H2 major conformer), 6.23–6.25 (1H,
f
Yield (0.50 g, 45%); yellow solid, mp 134–136 °C; R = 0.26
m, H3′ major conformer), 6.26–6.29 (2H, m, H3′ and H4′
minor conformer), 6.32–6.35 (2H, m, H2 minor conformer, H4′
major conformer), 7.29–7.33 (1H, m, H5′ minor conformer),
25
−1
(
EtOAc : MeOH; 9 : 1); [α]
D
= −190.5 (c = 1.0, CHCl
3
); νmax/cm
(
neat) 1656 (s, CvO), 1711 (s, CvO); δH (400 MHz, CD Cl ):
2
2
1
.36 (3H, t, J = 7.1 Hz, OCH
), 3.29 (1H, dd, J = 11.3, 7.1 Hz, H4
.1 Hz, OCH CH ), 4.76 (1H, app t, J = 7.6 Hz, H5), 6.22 (1H, s,
2
CH
3
), 3.02 (1H, dd, J = 11.3, 8.3
7
.38–7.42 (1H, m, H5′ major conformer); δ
CDCl ): 13.2 (OCH CH ), 31.2 and 33.1 (C4), 41.1 and 42.4
C2″), 51.8 and 52.6 (CO CH ), 58.0 and 58.5 (C2), 60.6 and
C
(100.6 MHz,
Hz, H4
7
A
B
), 4.37 (2H, q, J =
3
2
3
2
3
(
2
3
H2), 7.35 (1H, d, J = 8.1 Hz, H2′), 7.49 (2H, d, J = 8.6 Hz, H3′);
(100.6 MHz, CD Cl ): 14.5 (OCH CH ), 33.3 (C4), 62.3
OCH CH ), 62.3 (C2), 65.9 (C5), 99.5 (C7), 122.4 (C1′), 128.8
6
0.7 (OCH
2 3
CH ), 62.1 and 62.5 (C5), 105.2 and 106.4 (C3′),
δ
C
2
2
2
3
1
09.7 and 109.9 (C4′), 141.1 and 142.5 (C5′), 151.8 and 152.0
(
(
3
2
3
(
(
2
C1′), 164.1 (C1″), 165.7 and 166.3 (C3″), 168.8 and 169.5
−
C2′), 132.2 (C3′), 140.2 (C4′), 167.4 (C9), 186.5 (C6); m/z (ESI )
82 ([M − H] 100%) and 384 ([M − H] 100%); HRMS (ESI );
+
+
+
CO
6%); HRMS (ESI ); C14
requires 350.0669. Minor isomer (cis): yellow oil; R = 0.35
2
CH
3
); m/z (ESI ) 328 ([M + H] 100%), 350 ([M + Na]
−
−
−
+
+
H
17NNaO
6
S [M + Na] ; found 350.0677,
−
C H O NBrS [M − H] ; found 381.97563 and 383.97343,
1
5
13 4
f
requires 381.97541, 383.97337.
2
5
−1
(
(
(
EtOAc : petrol; 1 : 2); [α]
neat) 1665 (s, CvO), 1736 (s, CvO); δ
3H, t, J = 7.1 Hz, OCH CH ), 3.22–3.35 (2H, m, H4 , H4 ,
D
= +41.3 (c = 0.15, CHCl
3
); νmax/cm
H
3
(500 MHz, CDCl ) 1.27
(−)-(2S,5R)-1-Aza-7-ethoxycarbonyl-2-(4-fluorophenyl)-
2
3
A
B
6-hydroxy-8-oxo-3-thiabicyclo[3.3.0]oct-6-ene 9c
major conformer), 3.38 (1H, d, J = 15.4 Hz, H2″
conformer), 3.41–3.46 (2H, m, H4 /H4 and H2″
A
/H2″
/H2″
B
major
minor
Yield (0.46 g; 50%); yellow solid; R = 0.55 (EtOAc : MeOH;
f
A
B
A
B
2
5
−1
6
: 1); [α]
D
= −192.4, (c = 0.47, MeOH); νmax/cm (neat) 1224
conformer), 3.49–3.54 (1H, m, H2″ /H2″ minor conformer),
A
B
(
s, C–F), 1658 (s, CvO), 1710 (s, CvO); for 9c purified by pre-
3
(
.56 (2H, d, J = 15.5 Hz, H2″
1H, dd, J = 11.4, 4.8 Hz, H4 /H4
s, CO CH ), 4.13–4.25 (4H, m, OCH CH ), 4.91 (1H, dd, J = 9.0,
A
/H2″
B
major conformer), 3.64
parative TLC, δH (400 MHz, methanol-d ): 1.28 (3H, t, J = 7.0
4
A
B
minor conformer), 3.76 (3H,
2 3 A
Hz, OCH CH ), 2.95 (1H, dd, J = 11.0, 7.3 Hz, H4 ), 3.20 (1H,
2
3
2
3
dd, J = 11.0, 7.6 Hz, H4 ), 4.15–4.24 (2H, m, OCH CH and
B
2
3
6
.8 Hz, H5 major conformer), 4.96 (1H, dd, J = 6.8, 4.9 Hz,
H5 minor conformer), 6.18 (1H, s, H2 major conformer), 6.56
1H, s, H2 minor conformer), 6.26–6.29 (1H, m, H4′ minor con-
former), 6.34 (1H, dd, J = 3.2, 1.9 Hz, H4′ major conformer),
H5), 6.34 (1H, s, H2), 7.04 (2H, app t, J = 8.8 Hz, H3′), 7.47 (2H,
dd, J = 8.6, 5.4 Hz, H2′); δ (125.8 MHz, methanol-d ): 15.2
OCH CH ), 34.9 (C4), 59.7 (OCH CH ), 64.6 (C2), 70.6 (C5),
C
4
(
(
2
3
2
3
9
1
1
1.9 (C7), 116.0 (d, J = 21.9 Hz, C3′), 129.6 (d, J = 8.6 Hz, C2′),
6
3
.44 (1H, d, J = 3.2 Hz, H3′ minor conformer), 6.76 (1H, d, J =
.2 Hz, H3′ major conformer), 7.32–7.34 (1H, m, H5′ minor
39.8 (C1′), 163.7 (d, J = 244 Hz, C4′), 167.3 (C9), 180.2 (C8),
−
−
−
95.1 (C6); m/z (ESI ) 322 ([M − H] , 100%); HRMS (ESI );
conformer), 7.41 (1H, d, J = 1.3 Hz, H5′ major conformer);
(100.6 MHz, CDCl ): 14.0 (OCH CH ), 32.0 and 33.6 (C4),
1.8 and 42.4 (C2″), 52.7 and 53.1 (CO CH ), 58.7 and 59.29
−
C H FNO S [M − H] ; found 322.0552, requires 322.0555.
1
5
13
4
δ
C
3
2
3
4
2
3
(
8
−)-(2S,5R)-1-Aza-7-ethoxycarbonyl-6-hydroxy-2-(4-nitrophenyl)-
-oxo-3-thiabicyclo[3.3.0]oct-6-ene 9d
52.0 (C1′), 164.6 (C1″), 166.7 and 166.9 (C3″), 169.9 (CO CH ); Yield (0.32 g; 52%); yellow solid, mp 92 °C; R = 0.52 (EtOAc :
(C2), 61.7 (OCH
2 3
CH ), 62.7 and 63.4 (C5), 108.6 and 109.1
(C3′), 110.3 and 110.7 (C4′), 142.5 and 143.2 (C5′), 151.2 and
1
2
3
f
+
+
+
25
D
−1
m/z (ESI ) 328 ([M + H] 100%), 350 ([M + Na] 60%); HRMS MeOH; 6 : 1); [α]
= −222.2 (c = 0.35, CHCl
), 1517 (s, ArNO ), 1660 (s, CvO), 1711 (s,
CvO); δH (400 MHz, CD Cl ): 1.36 (3H, t, J = 7.2 Hz,
3
); νmax/cm (neat)
+
+
(ESI ); C14
H
17NNaO
6
S [M + Na] ; found 350.06688, requires 1344 (s, ArNO
2
2
3
50.06688.
2
2
OCH
J = 11.1, 7.2 Hz, H4
1H, app t, J = 7.6 Hz, H5), 6.32 (1H, s, H2), 7.63 (2H, d, J = 8.4
= 0.55 Hz, H2′), 8.19 (2H, d, J = 8.4 Hz H3′); δ (125.8 MHz, CD Cl ):
CH ), 33.5 (C4), 62.2 (C2), 62.4 (OCH CH ), 65.9
neat) 1617 (s, CvC), 1656 (s, CvO), 1712 (s, CvO); (C5), 99.7 (C7), 124.4 (C3′), 127.9 (C2′), 148.3 (C1′), 148.3 (C4′),
2
CH
3
), 3.05 (1H, dd, J = 10.9, 8.5 Hz, H4
A
), 3.31 (1H, dd,
(
−)-(2S,5R)-1-Aza-7-ethoxycarbonyl-6-hydroxy-8-oxo-2-phenyl-3-
B
), 4.38 (2H, q, J = 7.1 Hz, OCH
2
CH ), 4.79
3
thiabicyclo[3.3.0]oct-6-ene 9a
(
Yield (1.02 g, 43%); yellow solid, mp 88–90 °C; R
f
C
2
2
2
5
); νmax/cm−1 14.5 (OCH
(EtOAc : MeOH; 6 : 1); [α]
D
= −220.8 (c = 1.0, CHCl
3
2
3
2
3
(
−
−
δ
H
(400 MHz, CDCl
3
): 1.30 (3H, t, J = 7.1 Hz, OCH
), 3.19 (1H, dd, J = 11.0, 7.1 Hz, 100%); HRMS (ESI ); C15
H4 ), 4.30 (2H, q, J = 7.1 Hz, OCH CH ), 4.67 (1H, app t, J = 7.6 requires 349.0510.
2
CH
3
), 2.90 167.4 (C9), 169.2 (C8), 186.6 (C6); m/z (ESI ) 349 ([M − H] ,
−
−
(
1H, dd, J = 11.0, 8.1 Hz, H4
A
H
13
N
2
O
6
S [M − H] ; found 349.0500,
B
2
3
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Organic & Biomolecular Chemistry
(
−)-(2S,5R)-1-Aza-2-(2-Chloro-4-fluorophenyl)-7-
ethoxycarbonyl-6-hydroxy-8-oxo-3-thiabicyclo[3.3.0]oct-6-ene 9e 91.5 (C7), 115.3 (d, J = 21.9 Hz, C5′), 117.9 (d, J = 25.8 Hz, C3′),
29.2 (d, J = 8.6 Hz, C6′), 134.1 (d, J = 10.5 Hz, C2′), 138.3 (d,
J = 2.9 Hz, C1′), 163.2 (d, J = 248 Hz, C4′), 167.3 (C9), 179.7 (C8),
2 3 2 3
15.2 (OCH CH ), 34.2 (C4), 59.7 (OCH CH ), 62.3 (C2), 71.8 (C5),
1
f
Yield (0.48 g, 49%); yellow solid, mp 128 °C; R = 0.57 (EtOAc :
MeOH; 6 : 1); [α] = −264.0 (c = 0.20, CHCl ); νmax/cm (neat)
2
5
−1
D
3
−
−
−
1
C
95.0 (C6); m/z (ESI ) 356 ([M − H] , 100%); HRMS (ESI );
1
δ
233 (s, C–F), 1621 (s, CvC), 1658 (s, CvO), 1715 (s, CvO);
(400 MHz, CDCl ): 1.38 (3H, t, J = 7.1 Hz, OCH CH ), 2.99
1H, dd, J = 11.0, 8.8 Hz, H4 ), 3.28 (1H, dd, J = 11.0, 7.0 Hz,
−
15 4
H12ClFNO S [M − H] ; found 356.0172, requires 356.0165.
H
3
2
3
For ent-9e purified by flash column chromatography followed
(
A
25
by acid wash: [α] = +309.5 (c = 0.20, CHCl ); δH (400 MHz,
D
3
H4
.0 Hz, H5), 6.45 (1H, s, H2), 6.97 (1H, app td, J = 8.3, 2.5 Hz,
H5′), 7.13 (1H, dd, J = 8.3, 2.6 Hz, H3′), 7.38 (1H, dd, J = 8.6,
.9 Hz, H6′); δ (100.6 MHz, CDCl ): 14.1 (OCH CH ), 32.4
C4), 59.4 (C2), 61.8 (OCH CH ), 66.0 (C5), 98.8 (C7), 114.2 (d,
B 2 3
), 4.39 (2H, q, J = 7.1 Hz, OCH CH ), 4.91 (1H, dd, J = 8.8,
4 2 3
methanol-d ): 1.32 (3H, t, J = 7.1 Hz, OCH CH ), 3.03 (1H, dd,
7
A B
J = 10.9, 8.9 Hz, H4 ), 3.29–3.40 (1H, m, H4 ), 4.31 (2H, q, J =
7
.0 Hz, OCH CH ), 5.06 (1H, dd, J = 8.7, 7.0 Hz, H5), 6.39 (1H, s,
2
3
5
(
C
3
2
3
H2), 7.10 (1H, app td, J = 8.4, 2.6 Hz, H5′), 7.25 (1H, dd, J = 8.5,
.6 Hz, H3′), 7.57 (1H, dd, J = 8.8, 6.0 Hz, H6′).
2
3
2
J = 21.5 Hz, C5′), 117.4 (d, J = 25.4 Hz, C3′), 127.3 (d, J = 9.5 Hz,
C6′), 133.2 (d, J = 10.3 Hz, C2′), 134.3 (d, J = 3.2 Hz, C1′), 161.9
(
6
+)-(2S,5R)-1-Aza-2-(3-bromophenyl)-7-ethoxycarbonyl-
-hydroxy-8-oxo-3-thiabicyclo[3.3.0]oct-6-ene 9f
(
(
d, J = 250 Hz, C4′), 167.0 (C9), 167.9 (C8), 185.8 (C6); m/z
ESI ) 356 ([M − H] , 100%); HRMS (ESI ); C H ClFNO S
−
−
−
1
5
12
4
2
5
−
Yield (78%); R = 0.48 (EtOAc : MeOH; 4 : 1); [α] = +55.0 (c =
f: D
[M − H] ; found 356.0172, requires 356.0165.
.6 × 10− , MeOH); vmax/cm (neat) 1696 (CvO), 1622 (CvC);
(500 MHz, methanol-d ): 1.28 (3H, t, J = 7.1 Hz, OCH CH ),
.97 (1H, dd, J = 11.0, 7.3 Hz, H4 ), 3.20 (1H, dd, J = 11.0, 7.6
3
−1
1
δ
H
4
2
3
(
6
−)-(2S,5R)-1-Aza-2-(2-chloro-4-fluorophenyl)-7-ethoxycarbonyl-
-hydroxy-8-oxo-3-thiabicyclo[3.3.0]oct-6-ene 9e
Yield (0.03 g, 58%); yellow solid, mp 176–178 °C; R = 0.57
2
A
B 2 3
Hz, H4 ), 4.14–4.23 (3H, m, OCH CH and H5), 6.32 (1H, s,
H2), 7.24 (1H, app t, J = 7.9 Hz, H5′), 7.37–7.45 (2H, m, H4′
and H6′), 7.58–7.63 (1H, m, H2′); δC (125 MHz, methanol-d4)
f
−1
(EtOAc : MeOH; 6 : 1); νmax/cm (neat) 1236 (s, C–F), 1650 (s,
2
5
CvO), 1712 (s, CvO); for 9e purified by preparative TLC: [α]
=
D
2 3 2 3
15.2 (OCH CH ), 34.9 (C4), 59.6 (OCH CH ), 64.6 (C2), 70.7
−240.4 (c = 0.27, MeOH); δH (400 MHz, methanol-d ): 1.28
4
(
(
(
C5), 91.9 (C7), 123.4 (C3′), 126.5 (C4′/C6′), 130.6 (C2′), 131.3
(3H, t, J = 7.0 Hz, OCH
2
CH
3
), 2.95 (1H, dd, J = 11.0, 7.8 Hz,
C5′), 131.6 (C4′/C6′), 146.5 (C1′), 167.0 (C9), 180.2 (C8), 194.9
H4 ), 3.20 (1H, dd, J = 11.0, 7.3 Hz, H4 ), 4.14–4.23 (2H, m,
OCH CH ), 4.42 (1H, app t, J = 7.6 Hz, H5), 6.52 (1H, s, H2),
7
−
−
−
A
B
C6), m/z (ESI ) 382 ([M − H] ); HRMS (ESI ); C15
H
13BrNO
4
S
−
2
3
[M − H] ; found 381.9744, requires 381.9754.
.07 (1H, app td, J = 8.5, 2.3 Hz, H5′), 7.21 (1H, dd, J = 8.6, 2.7
Hz, H3′), 7.52 (1H, dd, J = 8.7, 6.0 Hz, H6′); δC (125.8 MHz, (−)-(2S,5R)-1-Aza-7-ethoxycarbonyl-2-(2-furanyl)-6-hydroxy-
methanol-d ): 15.2 (OCH CH ), 34.2 (C4), 59.7 (OCH CH ), 8-oxo-3-thiabicyclo[3.3.0]oct-6-ene 9g
4
2
3
2
3
6
(
2.3 (C2), 71.8 (C5), 91.5 (C7), 115.3 (d, J = 21.0 Hz, C5′), 117.9
d, J = 25.8 Hz, C3′), 129.2 (d, J = 8.6 Hz, C6′), 134.1 (d, J = 10.5
Hz, C2′), 138.3 (d, J = 2.9 Hz, C1′), 163.2 (d, J = 248 Hz, C4′),
Yield (1.53 g, 40%); brown oil; R = 0.30 (EtOAc : MeOH; 9 : 1);
f
25
−1
[
α]
D
= −153.3 (c = 0.06, CHCl
3
); νmax/cm (neat) 1614 (s,
(400 MHz, CD Cl ):
.36 (3H, t, J = 7.1 Hz, OCH CH ), 3.08 (1H, dd, J = 11.0, 6.9
CvC), 1663 (s, CvO), 1709 (s, CvO); δ
1
H
2
2
−
−
1
67.2 (C9), 179.7 (C8), 195.0 (C6); m/z (ESI ) 356 ([M − H] ,
2
3
−
−
1
00%); HRMS (ESI ); C H ClFNO S [M − H] ; found
1
5
12
4
Hz, H4
A
), 3.47 (1H, dd, J = 11.0, 8.1 Hz, H4
CH ), 4.83 (1H, app t, J = 7.5 Hz, H5), 6.30 (1H, s,
H2), 6.33–6.35 (2H, m, H3′and H4′), 7.40–7.43 (1H, m, H5′);
(125.8 MHz, CD Cl ): 14.5 (OCH CH ), 32.9 (C4), 56.3 (C2),
2.3 (OCH CH ), 65.2 (C5), 99.2 (C7), 107.5 (C3′), 110.9 (C4′),
43.5 (C5′), 153.4 (C1′), 167.4 (C9), 168.8 (C8), 187.2 (C6); m/z
B
), 4.37 (2H, q, J =
3
56.0170, requires 356.0165. For 9e purified by flash column
7.1 Hz, OCH
2
3
2
5
chromatography followed by acid wash: [α]
CHCl ); δ (400 MHz, methanol-d ): 1.32 (3H, t, J = 7.1 Hz,
D
= −331.8 (c = 0.27,
3
H
4
δ
C
2
2
2
3
OCH
m, H4
.8, 6.9 Hz, H5), 6.39 (1H, s, H2), 7.10 (1H, app td, J = 8.5, 2.6
Hz, H5′), 7.25 (1H, dd, J = 8.5, 2.6 Hz, H3′), 7.58 (1H, dd, J =
.7, 6.0 Hz, H6′).
2
CH
3
A
), 3.04 (1H, dd, J = 11.0, 8.9 Hz, H4 ), 3.29–3.40 (1H,
6
1
2
3
B
), 4.31 (2H, q, J = 7.0 Hz, OCH
2
CH ), 5.05 (1H, dd, J =
3
8
−
−
−
(
ESI ) 294 ([M − H] , 50%); HRMS (ESI ); C13
H12NO
5
S
−
[M − H] ; found 294.0446, requires 294.0442.
8
(
±)-(2RS,5R)- 2-(4-Fluorophenyl)-5-methoxycarbonyl-
1,3-thiazolidine (±)-7c
Yield (0.42 g, 43%); colourless oil; 1.7 : 1 cis and trans diastereo-
(
6
+)-(2R,5S)-1-Aza-2-(2-chloro-4-fluorophenyl)-7-ethoxycarbonyl-
-hydroxy-8-oxo-3-thiabicyclo[3.3.0]oct-6-ene ent-9e
Yield (0.033 g, 6%); yellow solid; R = 0.57 (EtOAc : MeOH; mers; R
: 1); νmax/cm (neat) 1232 (s, C–F), 1656 (s, CvO), 1709 (s, C–F), 1741 (s, CvO), 3315 (m, N–H); δ
−
1
f
f
= 0.35 (EtOAc : petrol; 1 : 3); νmax/cm (neat) 1223 (s,
(200 MHz, CDCl
CvO); for ent-9e purified by preparative TLC; [α]D = +230.3 major isomer (cis): 2.57 (1H, br. s., NH), 3.05–3.26 (1H, m,
c = 0.38, MeOH); δ (400 MHz, methanol-d ): 1.28 (3H, t, J = H4 ), 3.33–3.53 (1H, m, H4 ), 3.81 (3H, s, CO CH ), 3.99 (1H,
.0 Hz, OCH CH ), 2.95 (1H, dd, J = 10.7, 8.0 Hz, H4 ), 3.20 dd, J = 8.8, 7.1 Hz, H5), 5.53 (1H, s, H2), 6.96–7.12 (2H, m,
1H, J = 10.7, 7.5 Hz, H4 ), 4.19 (2H, q, J = 7.0 Hz, OCH CH ), H3′), 7.43–7.56 (2H, m, H2′); minor isomer (trans): 2.57 (1H,
−
1
6
H
3
)
2
5
(
7
(
H
4
A
B
2
3
2
3
A
B
2
3
4
.43 (1H, app t, J = 7.21 Hz, H5), 6.52 (1H, s, H2), 7.07 (1H, br. s., NH), 3.05–3.26 (1H, m, H4
), 3.80 (3H, s, CO CH ), 4.14–4.23 (1H, m, H5), 5.79 (1H, s,
.51 (1H, dd, J = 8.7, 6.0 Hz, H6′); δ (125.8 MHz, methanol-d ): H2), 6.96–7.12 (2H, m, H3′), 7.43–7.56 (2H, m, H2′);
A
), 3.33–3.53 (1H, m, Hz,
app td, J = 8.5, 2.6 Hz, H5′), 7.21 (1H, dd, J = 8.5, 2.6 Hz, H3′), H4
7
B
2
3
C
4
Org. Biomol. Chem.
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Organic & Biomolecular Chemistry
Paper
−
−
−
δ
C
(100.6 MHz, CDCl
3
) major isomer (cis): 39.2 (C4), 52.6 ([M − H] , 100%); HRMS (ESI ); C15
H
13FNO
4
S [M − H] ; found
(
(
CO CH ), 65.4 (C5), 71.8 (C2), 115.5 (d, J = 21.5 Hz, C3′), 129.3 322.0569, requires 322.0555.
2
3
d, J = 8.7 Hz, C2′), 133.9 (d, J = 3.2 Hz, C1′), 162.8 (d, J = 247
CH ); minor isomer (trans): 38.0 (C4), 52.6
CO CH ), 64.1 (C5), 69.9 (C2), 115.1 (d, J = 21.5 Hz, C3′), 128.7
(
1
±)-(2RS,5R)-2-(2-Chloro-4-fluorophenyl)-5-methoxycarbonyl-
,3-thiazolidine (±)-7e
d, J = 8.0 Hz, C2′), 136.9 (d, J = 3.2 Hz, C1′), 162.3 (d, J = 247 Yield 51% (1.15 g); colourless oil; 0.9 : 1 cis and trans diastereo-
Hz, C4′), 171.5 (CO
(
(
2
3
2
3
+
+
−1
Hz, C4′), 172.1 (CO
2
CH
3
); m/z (ESI ) 242 ([M + H] , 100%); mers; R
f
= 0.18 (EtOAc : petrol; 1 : 5); νmax/cm (neat) 1227 (s,
+
+
HRMS (ESI ); C H FNO S [M + H] ; found 242.0642, requires C–F), 1738 (s, CvO), 3324 (m, N–H); δH (400 MHz, CDCl3)
1
1
13
2
2
42.0646.
major isomer (trans): 2.66 (1H, br. s., NH), 3.06–3.14 (1H, m,
H4 ), 3.33 (1H, dd, J = 10.5, 6.4 Hz, H4 ), 3.81 (3H, s, CO CH ),
.21 (1H, app t, J = 6.6 Hz, H5), 6.02 (1H, s, H2), 6.95 (2H, app
td, J = 8.3, 2.7 Hz, H5′), 7.08–7.15 (2H, m, H3′), 7.57 (2H, dd,
J = 8.7, 6.2 Hz, H6′); minor isomer (cis): 2.66 (1H, br. s., NH),
A
B
2
3
4
(
5
±)-(2RS,5R)-(3-Ethoxy-3-oxopropanoyl)-2-(4-fluorophenyl)-
-methoxycarbonyl-1,3-thiazolidine (±)-8c
Yield (0.43 g, 81%); colourless oil; 1.3 : 1 cis and trans diastereo-
3
3
7
7
.06–3.14 (1H, m, H4 ), 3.45 (1H, dd, J = 10.3, 6.9 Hz, H4 ),
A B
.80 (3H, s, CO CH ), 3.96–4.04 (1H, m, H5), 5.88 (1H, s, H2),
2 3
.03 (2H, app td, J = 8.3, 2.7 Hz, H5′), 7.08–7.15 (2H, m, H3′),
.74 (2H, dd, J = 8.7, 6.0 Hz, H6′); δC (100.6 MHz, CDCl3):
−
1
mers; R = 0.61 (EtOAc : petrol; 1 : 1); νmax/cm (neat) 1224
f
H 3
(s, C–F), 1662 (s, CvO), 1740 (s, CvO); δ (400 MHz, CDCl )
major isomer (cis, a mixture of conformers): 1.19–1.31 (3H, m,
OCH CH ), 3.07–3.55 (4H, m, H4 , H4 , H2″ , H2″ ), 3.81 and
3
2
3
A
B
A
B
major isomer (trans): 37.3 (C4), 52.6 (CO
2
CH
3
), 64.7 (C5), 66.5
2 3 2 3
.83 (3H, s, CO CH ), 4.05–4.24 (2H, m, OCH CH ), 5.03–5.08
(
C2), 113.8 (d, J = 21.5 Hz, C5′), 117.0 (d, J = 25.4 Hz, C3′),
(
(
1H, m, H5), 6.13 and 6.30 (1H, s, H2), 6.95–7.01 and 7.04–7.10
2H, m, H3′), 7.48–7.54 and 7.64–7.69 (2H, m, H2′); minor
1
27.8 (d, J = 8.7 Hz, C6′), 133.5 (d, J = 10.3 Hz, C2′), 136.1 (d,
CH );
), 65.3 (C5), 67.6
C2), 114.5 (d, J = 20.7 Hz, C5′), 117.1 (d, J = 24.6 Hz, C3′),
J = 4.0 Hz, C1′), 161.6 (d, J = 250 Hz, C4′), 171.9 (CO
minor isomer (cis): 38.7 (C4), 52.6 (CO CH
(
2
3
isomer (trans, a mixture of conformers): 1.19–1.31 (3H, m,
OCH CH ), 3.07–3.55 (4H, m, H4 , H4 , H2″ , H2″ ), 3.78 and
3
and 5.28–5.31 (1H, m, H5), 6.17 and 6.29 (1H, s, H2), 6.95–7.01
and 7.04–7.10 (2H, m, H3′), 7.19–7.23 and 7.24–7.29 (2H, m,
H2′); δC (100.6 MHz, CDCl ) major isomer (cis, a mixture of
2
3
2
3
A
B
A
B
.84 (3H, s, CO CH ), 4.05–4.24 (2H, m, OCH CH ), 5.17–5.21
2 3 2 3
1
1
29.7 (d, J = 8.7 Hz, C6′), 131.9 (d, J = 3.2 Hz, C1′), 134.5 (d, J =
0.3 Hz, C2′), 162.1 (d, J = 251 Hz, C4′), 171.4 (CO CH ); m/z
2
3
+
+
+
(
ESI ) 276 ([M + H] 100%); HRMS (ESI ); C H ClFNNaO S
11 11 2
3
+
[M + Na] ; found 298.0079, requires 298.0075.
conformers): 13.9 and 14.0 (OCH
2
CH
3
), 32.0 and 33.8 (C4),
4
6
2.1 and 43.0 (C2″), 52.8 and 53.1 (CO CH ), 61.5, 61.6 and
2
3
(±)-(2RS,5R)-2-(2-Chloro-4-fluorophenyl)-(3-ethoxy-3-
oxopropanoyl)-5-methoxycarbonyl-1,3-thiazolidine (±)-8e
1.8 (OCH CH ), 63.7 and 64.6 (C5), 65.7 and 66.4 (C2), 115.0
2
3
(
8
d, J = 21.5 Hz, C3′) and 115.9 (d, J = 21.5 Hz, C3′), 128.4 (d, J =
.0 Hz, C2′) and 129.0 (d, J = 8.7 Hz, C2′), 135.6 (d, J = 2.4 Hz,
C1′), 162.6 (d, J = 249 Hz, C4′), 165.4 (C1″), 166.6 (C3″), 170.2
CO CH ); minor isomer (trans, a mixture of conformers): 13.9
and 14.0 (OCH CH ), 30.9 and 33.0 (C4), 42.3 and 43.3 (C2″),
Yield (0.73 g, 94%); 0.7 : 1 separable cis and trans diastereo-
mers; major isomer (trans, a mixture of conformers): white
−
1
solid, mp 82–84 °C; R
neat) 1225 (s, C–F), 1668 (s, CvO), 1743 (s, CvO);
δ (400 MHz, CDCl ): 1.23 (3H, t, J = 7.1 Hz, OCH CH major con-
f
= 0.16 (EtOAc : petrol; 1 : 3); νmax/cm
(
2
3
(
2
3
H
3
2
3
5
2.8 and 53.4 (CO CH ), 61.5, 61.6 and 61.8 (OCH CH ), 64.0
2 3 2 3
former), 1.31 (3H, t, J = 7.2 Hz, OCH
.06–3.48 (4H, m, H4 , H4 , H2″ , H2″
major conformer), 3.87 (3H, s, CO CH minor conformer), 4.10
2
CH
3
minor conformer),
and 64.2 (C5), 64.4 and 65.1 (C2), 115.3 (d, J = 22.3 Hz, C3′)
and 116.2 (d, J = 21.5 Hz, C3′), 126.5 (d, J = 8.7 Hz, C2′) and
1
2
(
3
A
B
A
B
), 3.81 (3H, s, CO
2
CH
3
2
3
26.7 (d, J = 8.0 Hz, C2′), 137.9 (d, J = 2.4 Hz, C1′), 162.5 (d, J =
48 Hz, C4′), 165.3 (C1″), 166.2 (C3″), 169.3 (CO CH ); m/z
(
2H, q, J = 7.1 Hz, OCH
2 3
CH major conformer), 4.18–4.27 (2H,
2
3
m, OCH CH minor conformer), 5.20–5.23 (1H, m, H5 minor
2
3
+
+
+
+
ESI ) 356 ([M + H] , 100%) 378 ([M + Na] , 94%); HRMS (ESI );
conformer), 5.30–5.34 (1H, m, H5 major conformer), 6.44 (1H,
s, H2 major conformer), 6.47 (1H, s, H2 minor conformer),
+
C H FNNaO S [M + Na] ; found 378.0797, requires 378.0782.
1
6
18
5
6
.94 (1H, app td, J = 8.4, 2.6 Hz, H5′ minor conformer), 7.03
(
6
±)-(2S,5R)-1-Aza-7-ethoxycarbonyl-2-(4-fluorophenyl)-
-hydroxy-8-oxo-3-thiabicyclo[3.3.0]oct-6-ene (±)-9c
(
1H, J = 8.3, 2.6 Hz, H5′ major conformer), 7.12–7.18 (2H, m,
H3′ minor conformer, H6′ major conformer), 7.21 (1H, dd, J =
Yield (0.12 g, 53%); yellow solid; R
f
= 0.55 (EtOAc : MeOH; 8.2, 2.6 Hz, H3′ major conformer), 7.33 (1H, dd, J = 8.6, 5.9 Hz,
−
1
6
: 1); νmax/cm (neat) 1224 (s, C–F), 1658 (s, CvO), 1709 (s, H6′ minor conformer); δC (100.6 MHz, CDCl ): 13.9 and 14.0
3
CvO); for (±)-9c purified by preparative TLC, δ
H
(400 MHz, (OCH
2
CH
3
), 30.6 and 32.5 (C4), 42.1 and 43.1 (C2″), 52.9 and
), 61.6 and 61.9 (OCH CH ), 62.0 and 62.9 (C2),
methanol-d ): 1.28 (3H, t, J = 7.1 Hz, OCH CH ), 2.95 (1H, dd, 53.5 (CO
4
2
3
2
CH
3
2
3
J = 11.0, 7.3 Hz, H4 ), 3.20 (1H, dd, J = 11.0, 7.6 Hz, H4 ), 64.3 and 64.6 (C5), 113.8 (d, J = 20.7 Hz, C5′) and 114.5 (d, J =
A
B
4
.14–4.24 (3H, m, OCH
2
CH
3
, H5), 6.34 (1H, s, H2), 7.04 (2H, 21.5 Hz, C5′), 117.5 (d, J = 24.6 Hz, C3′) and 118.0 (d, J = 24.6
app t, J = 8.8 Hz, H3′), 7.47 (2H, dd, J = 8.6, 5.4 Hz, H2′); Hz, C3′), 125.7 (d, J = 8.7 Hz, C6′) and 126.4 (d, J = 8.7 Hz, C6′),
δ (125.8 MHz, methanol-d ): 15.2 (OCH CH ), 34.9 (C4), 59.7 132.6 (d, J = 10.3 Hz, C2′), 134.6 (d, J = 3.2 Hz, C1′) and 134.7
C
4
2
3
2 3
(OCH CH ), 64.6 (C2), 70.6 (C5), 91.9 (C7), 116.0 (d, J = 21.9 (d, J = 3.2 Hz, C1′), 161.6 (d, J = 250 Hz, C4′) and 162.1 (d, J =
Hz, C3′), 129.6 (d, J = 8.6 Hz, C2′), 139.8 (C1′), 163.7 (d, J = 244 252 Hz, C4′), 164.5 and 165.1 (C1″), 166.0 and 167.5 (C3″),
−
+
+
Hz, C4′), 167.3 (C9), 180.2 (C8), 195.1 (C6); m/z (ESI ) 322 169.2 and 170.1 (CO CH ); m/z (ESI ) 390 ([M + H] 100%),
2
3
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12.0 ([M + Na] 65%); HRMS (ESI ); C16
Organic & Biomolecular Chemistry
+
+
−
−
NBrS [M − H]−;
4
H
17ClFNNaO
5
S [M + ([M − H] , 100%); HRMS (ESI ); C15
H
13
O
4
+
Na] ; found 412.0398, requires 412.0392. Minor isomer (cis, a found 381.97573 and 383.97348, requires 381.97541,
mixture of conformers): colourless oil; R = 0.24 (EtOAc : petrol; 383.97337.
: 3); νmax/cm (neat) 1224 (s, C–F), 1664 (s, CvO), 1740 (s,
f
−
1
1
CvO); δH (400 MHz, CDCl ): 1.21–1.30 (3H, m, OCH CH ),
3
2
3
3
.07–3.54 (4H, m, H4
A
, H4
B
, H2″
A
, H2″
B
), 3.85 (3H, s, CO
2
CH
3
Acknowledgements
major conformer), 3.89 (3H, s, CO
2 3
CH minor conformer),
4
.09–4.22 (2H, m, OCH CH ), 4.91 (1H, dd, J = 9.2, 6.5 Hz, We are particularly grateful for access to chiral chromato-
2
3
H5 major conformer), 5.06 (1H, app t, J = 5.0 Hz, H5 minor graphy made available by Professors Martin Smith and Mike
conformer), 6.38 (1H, s, H2 major conformer), 6.52 (1H, s, Willis (University of Oxford). We also wish to acknowledge
H2 minor conformer), 6.95 (1H, app t, J = 8.3 Hz, H5′ minor financial support from the FfWG and from an MRC Confi-
conformer), 7.08 (1H, app td, J = 8.3, 2.3 Hz, H5′ major confor- dence in Concept award. SI thanks HEC Pakistan for a
mer), 7.17 (1H, dd, J = 8.1, 2.4 Hz, H3′), 7.84 (1H, dd, J = 8.7, scholarship.
6
.0 Hz, H6′ minor conformer), 8.28 (1H, dd, J = 8.7, 6.0 Hz, H6′
major conformer); δ (100.6 MHz, CDCl ): 14.0 (OCH CH ),
1.2 and 33.8 (C4), 41.8 and 42.8 (C2″), 52.8 and 53.3
C
3
2
3
3
References
(CO CH ), 61.7 (OCH CH ), 62.9 and 64.5 (C2), 64.2 and 65.2
2 3 2 3
(
1
(
1
C5), 114.3 (d, J = 20.7 Hz, C5′) and 114.7 (d, J = 20.7 Hz, C5′),
16.7 (d, J = 25.4 Hz, C3′) and 117.4 (d, J = 25.4 Hz, C3′), 128.3
d, J = 8.0 Hz, C6′) and 128.9 (d, J = 8.7 Hz, C6′), 132.7 (d, J =
0.3 Hz, C2′), 133.7 (d, J = 4.0 Hz, C1′), 162.2 (d, J = 252 Hz,
C4′), 165.1 and 165.3 (C1″), 166.2 and 166.8 (C3″), 170.3 and
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+
+
1
70.4 (CO CH ); m/z (ESI ) 390 ([M + H] 100%), 412.0
2 3
+
+
+
([M + Na] 71%); HRMS (ESI ); C16
H
17ClFNNaO
5
S [M + Na] ;
4 M. Anwar, A. R. Cowley and M. G. Moloney, Tetrahedron:
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5
L. Josa-Culleré, M. G. Moloney and A. L. Thompson,
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(
6
±)-(2S,5R)-1-Aza-2-(2-Chloro-4-fluorophenyl)-7-ethoxycarbonyl-
-hydroxy-8-oxo-3-thiabicyclo[3.3.0]oct-6-ene (±)9e
Yield (74 mg, 45%); yellow solid, mp 96–98 °C; R = 0.57
6
f
−1
(
EtOAc : MeOH; 6 : 1); νmax/cm (neat) 1230 (s, C–F), 1658 (s,
CvO), 1707 (s, CvO); δ (500 MHz, CD Cl ): 1.37 (3H, t, J =
.2 Hz, OCH CH ), 3.01 (1H, dd, J = 11.0, 8.8 Hz, H4 ), 3.30
H
2
2
7 D. Seebach, A. R. Sting and M. Hoffmann, Angew. Chem.,
Int. Ed. Engl., 1996, 35, 2708–2748.
7
2
3
A
(
1H, dd, J = 11.0, 6.9 Hz, H4
OCH CH ), 4.91–4.95 (1H, m, H5), 6.41 (1H, s, H2), 7.03 (1H,
app td, J = 8.4, 2.6 Hz, H5′), 7.17 (1H, dd, J = 8.4, 2.6 Hz, H3′),
.42 (1H, dd, J = 8.6, 6.0 Hz, H6′); δ (125 MHz, CD Cl ): 14.5
OCH CH ), 33.0 (C4), 59.9 (OCH CH
9.5 (C7), 114.9 (d, J = 21.9 Hz, C5′), 117.8 (d, J = 25.8 Hz, C3′),
28.0 (d, J = 8.6 Hz, C6′), 133.6 (d, J = 10.5 Hz, C2′), 135.4 (d, 11 W. Flitsch, Chem. Ber., 1970, 103, 3205–3213.
B
), 4.39 (2H, q, J = 7.2 Hz,
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9 J. H. Bailey, D. Cherry, J. Dyer, M. G. Moloney,
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2
3
7
(
9
1
C
2
2
2
3
2
3
), 62.4 (C2), 66.6 (C5), 10 S. A. Hermitage and M. G. Moloney, Tetrahedron:Asymmetry,
1994, 1463–1464.
J = 3.8 Hz, C1′), 162.6 (d, J = 250 Hz, C4′), 167.5 (C9), 168.3 12 M. Anwar and M. G. Moloney, Chem. Biol. Drug Des., 2013,
−
−
(
(
C8), 186.5 (C6); m/z (ESI ) 356 ([M − H] , 100%); HRMS
81, 645–649.
+
+
ESI ); C15
H
14
O
4
NClFS [M + H] ; found 358.03120, requires 13 F. Fulop, J. Mattinen and K. Pihlaja, Tetrahedron, 1990, 46,
3
58.03106.
6545–6552.
1
1
4 M. D. Andrews, A. Brewster and M. G. Moloney, Tetra-
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(
±)-(2S,5R)-1-Aza-2-bromophenyl-7-ethoxycarbonyl-6-hydroxy-8-
oxo-3-thiabicyclo[3.3.0]oct-6-ene (±)9b
5 Single crystal X-ray diffraction data were collected at 150 K
with an Oxford Diffraction (Rigaku) SuperNova diffracto-
meter (using λ = 1.54180 Å) and processed with CrysAlisPro
Yield (47 mg, 39%); yellow solid, mp 148 °C; R = 0.26 (EtOAc :
f
−
1
MeOH; 9 : 1); νmax/cm (neat) 1618 (CvC), 1657 (s, CvO),
712 (s, CvO); δ (500 MHz, CD Cl ): 1.37 (3H, t, J = 7.2 Hz,
2
5
1
H
2
2
as per the ESI (CIF).† The structure was solved with SIR92
and refined with CRYSTALS.
2
6,27
OCH CH ), 3.02 (1H, dd, J = 11.2, 8.2 Hz, H4 ), 3.29 (1H, dd,
Full crystallographic data
2
3
A
J = 11.2, 7.1 Hz, H4
B
), 4.38 (2H, q, J = 7.2 Hz, OCH
2
CH
3
), 4.76
(in CIF format) is available as ESI† and has been deposited
with the Cambridge Crystallographic Data Centre (refer-
ence code CCDC 1452987).
(1H, app t, J = 7.6 Hz, H5), 6.22 (1H, s, H2), 7.35 (2H, d, J = 8.3
Hz, H2′), 7.49 (2H, d, J = 8.5 Hz, H3′); δC (125 MHz, CD Cl ):
2
2
1
4.5 (OCH
2 3 2 3
CH ), 33.4 (C4), 62.3 (OCH CH ), 62.4 (C2), 65.8 16 F. Fulop and K. Pihlaja, Tetrahedron, 1993, 49, 6701–6706.
(
1
C5), 99.7 (C7), 122.4 (C1′), 128.8 (C2′), 132.2 (C3′), 140.3 (C4′), 17 F. Fulop, K. Pihlaja, J. Mattinen and G. Bernath, J. Org.
−
67.5 (C9), 169.1 (C8), 186.6 (C6); m/z (ESI ) 382.0 and 384.0
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Org. Biomol. Chem.
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