Studies towards the total synthesis of batzelladine A

Article abstract of DOI:10.1039/b404679j

Application of a diastereoselective three-component coupling to the bicyclic core of the batzelladine alkaloids is described. The synthesis features the elaboration of glutamic acid by use of Eschenmoser sulfide contraction. An earlier approach is also included, which shows some limitations of dithiane chemistry when applied to the particular compounds required for this target.

Full text of DOI:10.1039/b404679j

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Studies towards the total synthesis of batzelladine A
Mark C. Elliott* and Matthew S. Long
School of Chemistry, Cardiff University, PO Box 912, Cardiff, UK CF10 3TB.
E-mail: elliottmc@cardiff.ac.uk; Fax: 44 (0)29 2087 4030; Tel: 44 (0)29 20874686
Received 29th March 2004, Accepted 21st May 2004
First published as an Advance Article on the web 28th June 2004
Application of a diastereoselective three-component coupling to the bicyclic core of the batzelladine alkaloids
is described. The synthesis features the elaboration of glutamic acid by use of Eschenmoser sulfide contraction.
An earlier approach is also included, which shows some limitations of dithiane chemistry when applied to the
particular compounds required for this target.
Introduction
The batzelladine alkaloids form part of a structurally and bio-
logically fascinating group of natural products obtained from
marine sources. The first of these compounds, batzelladines
A–E, were isolated in 1995 and possess a range of interesting
and useful biological activity. In particular, batzelladines A (1)
and B (2) inhibit the binding of HIV glycoprotein gp120 to
the CD4 receptor and so are of therapeutic interest for the
treatment of HIV. Batzelladines C–E, of which batzelladine D
(3) is structurally representative, are cytotoxic.1 Subsequent
studies led to the isolation of four further alkaloids, named
batzelladines F–I, each containing two of the tricyclic units
found in batzelladines A–E [e.g. batzelladine F (4)].2 These
compounds possess structural similarities to a number of other
alkaloids, for example, crambescin A (crambine A) (5)3 and
ptilomycalin A (6).4
These compounds have been the subject of numerous
synthetic studies, leading to the development of a wealth of
new methodology. The first approach was developed extremely
quickly, and features a relatively long linear sequence in the
synthesis of the tricyclic cores of batzelladines B and D.5 Snider
and Murphy’s groups have independently reported (presum-
ably) biomimetic approaches to the same tricyclic core.6 This
work has led to one total synthesis,7 and much structural
revision.8 Overman and co-workers have developed tethered
Biginelli cyclisations giving bicyclic and tricyclic guanidines,9,10
culminating in the total syntheses of batzelladines D11 and F,12
and also
a particularly rapid synthesis of symmetrical
analogues.13 Batzelladine D has also been synthesised by
Nagasawa’s group.14 Most of the synthetic work has been
directed towards the tricyclic portion of these natural products,
one notable exception being a report from the group of Gin
in Illinois, who have elucidated the previously unknown
stereochemistry of the bicyclic portion of batzelladine A (which
is presumably the same as batzelladine B).15 Very recently,
Nagasawa’s group have completed the total synthesis of
batzelladine A.16
In recent years we have developed asymmetric annulation
reactions of azolines with heterocumulenes,17 leading to a
stereoselective preparation of fused pyrimidines and piper-
idines. For example, reaction of oxazoline 7 with phenyl
isocyanate gives compound 8 in high yield and with complete
diastereocontrol (Scheme 1).18 Comparison of compound 8
with the batzelladine alkaloids shows considerable similarity
in the placement of heteroatoms and stereogenic centres. Our
initial disconnection is shown in Scheme 2, in which the core
pyrrolo[1,2-c]pyrimidine 10 would be derived from a formal
hetero-Diels–Alder reaction of alkenylpyrroline 9 with a suit-
able heterocumulene. In principle, this could then be followed
by acylation with a suitable chloroformate, to give 11.19 Ideally,
‘X’ would be nitrogen, but we had previously found that the
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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taken to avoid heating during the reduction step and
subsequent work-up, variable amounts of lactone 16 were
formed. This compound could be prepared as the sole product
simply by heating the crude alcohol 14 (Scheme 3).
Scheme 1
Scheme 3 Reagents and conditions: i, NaBH4, EtOH, 0 ЊC, 18 h; ii,
CH3SO2Cl, Et3N, CH2Cl2, 0 ЊC, 3 h; iii, NaBH4, EtOH, 0 ЊC, 16 h then
EtOAc, reflux, 2 h.
1,3-Dithiane 17 underwent ready acylation with ethyl acetate
to give 18. Unfortunately, deprotonation (n-BuLi, LiHMDS,
NaH) of either 17 or 18 and reaction with mesylate 15 gave
none of the desired products (Scheme 4).
Scheme 2
formal aza-Diels–Alder reactions with carbodiimides were
sluggish, and so we chose to pursue the case where X = sulfur
with a view to converting the thiourea into the corresponding
guanidine.20
Alkenylpyrrolines are extremely rare, and would be expected
to exist in equilibrium with the enamine tautomers. Since the
annulation reaction which we are using proceeds in a stepwise
manner, it seemed probable that either tautomer would react in
a similar manner. However, the safer option was to block the
pyrroline at the 3-position. Our choice of a dithiane as blocking
group dictated much of our initial approach to the batzelladine
alkaloids, as described in the following section.
Results and discussion
Scheme 4 Reagents and conditions: i, n-BuLi, Ϫ40 ЊC, 1 h then EtOAc.
Route 1 – the dithiane approach
This unfortunate result prompted a change to the synthetic
strategy. We had originally envisaged carrying out the aldol
reaction after imine formation in order to avoid competing
conjugate addition (see structure 12). As an alternative, if the
imine formation was carried out by an aza-Wittig reaction,
conjugate addition should not be a problem. In order to realise
this scenario, we required a suitable azide which was to
be prepared by standard displacement of a mesylate. Ring-
opening of glycidol TBS ether 19a with the anion derived from
deprotonation of 1,3-dithiane 17 gave alcohol 20a. Activation
of this secondary alcohol as the mesylate 21a was followed by
displacement with azide to give 22a (Scheme 5).
As our initial target for model studies we chose compound 12,
shown below with the relevant disconnections in their intended
order of bond formation (Fig. 1). Aspartic acid was chosen as
starting material since compound 12 will then contain the latent
functionality to allow formation of the third ring in the tricyclic
portion of the batzelladine alkaloids.
Deprotonation of 22a and reaction with crotonaldehyde gave
a somewhat confusing result. Although there was some
indication that the required allylic alcohol had been introduced,
we were concerned by the lack of azide functionality in the IR
spectrum, and also by the clear loss of the TBS protecting
group in the proton NMR spectrum. Given the loss of protect-
ing group, the most obvious course of action was to repeat
this sequence with an alternative protecting group. This was
accomplished starting with benzyl glycidyl ether 19b (also
shown in Scheme 5).
Fig. 1 Retrosynthetic analysis.
The Cbz-protected diethyl ester of aspartic acid 13 was
prepared in routine manner. From this point, regioselective
reduction of the α-aminoester gave alcohol 14 which was
readily converted into the mesylate ester 15. If care was not
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Scheme 5 Reagents and conditions: i, 1,3-dithiane, n-BuLi, THF
Ϫ40 ЊC then 19a or 19b, Ϫ40 ЊC, 2 h; ii, CH3SO2Cl, Et3N, CH2Cl2, 0 ЊC,
3 h; iii, NaN3, DMSO, sealed tube, 80 ЊC, 72 h.
Scheme 7
Unfortunately, once again, deprotonation of 22b and
reaction with crotonaldehyde gave a complex mixture of the
products, and we were unable to obtain any evidence that the
desired compound had been formed.
Route 2 – three-component coupling21
Since the initial route presented us with problems, and the
solutions which we considered would render it long-winded, we
decided on a substantially modified approach which should still
retain the advantages of a formal aza-Diels–Alder reaction. For
this purpose, we chose to investigate a diastereoselective version
of a reaction used by Kishi and co-workers for the synthesis of
saxitoxin.22 The key step was the three-component coupling
of an alkylidenepyrrolidine, an aldehyde and an isothiocyanate
to give the key pyrrolo[1,2-c]pyrimidine (Scheme 6).
Scheme 8
Scheme 6
giving the annulation precursor 29, the double bond geometry
of which was confirmed by NOE studies (Scheme 9).
Although the reaction shown features a 1,3-dioxane which
functions as a blocking group, subsequent work by Kishi and
Hong showed that this is not actually necessary, and in fact
diastereoselective annulations were reported using chiral
aldehydes.23 There are two distinct mechanistic possibilities for
the final ring-closure step. The first possibility is directly analo-
gous to the ring-closure step in the formal aza-Diels–Alder
reaction of alkenylazolines with isocyanates, and would be
expected to lead to high diastereoselectivity via a transition
state shown in Scheme 7.24 The alternative should also give the
same major diastereoisomer, this time via the transition state
shown in Scheme 8. As in our previous work, the stereo-
chemical outcome is guided by the heterocumulene heteroatom
(in this case sulfur) avoiding close contact with the substituent
on the azoline ring.
The key annulation was initially attempted with benzoyl
isothiocyanate and acetaldehyde. However, instead of the
desired compound, 30 was formed in low yield as a single
double bond isomer. The same compound can be formed in
higher yield if the acetaldehyde is omitted (Scheme 10).
This contrasts with an earlier report in which N-acylation is
observed with similar substrates,27 although on inspection of
the spectroscopic data, we have some concerns about the
structural assignments in this work. For instance, for com-
pound 31 the chemical shift of the alkene hydrogen was
reported as 7.6 ppm, while that in compound 32 is reported as
6.5 ppm. Additionally, these compounds give peaks assigned to
N–H hydrogens at 7.3 and 5.4 ppm respectively. In comparison,
the alkene hydrogen in compound 29 resonates at 4.5 ppm.
Comparison with other examples in the literature shows that
for compound 32 the reported shift is typical, whereas that in 31
seems to us to be too high.28 The differing reaction conditions
for the formation of the two compounds should also be con-
sidered. Compound 31 was formed under reflux (benzene)
whereas 32 was formed at room temperature. It is reasonable to
expect C-acylation in the former case and possibly N-acylation
in the latter.17 Closer examination of the data lead us to suggest
that the compound assigned structure 31 is most probably
33, with the peaks at 7.3 and 7.6 ppm both being due to
N–H resonances. Unfortunately the 13C-NMR data, and also
With this in mind, the synthetic strategy simply involved
preparation of
a suitable alkylidenepyrrolidine and its
evaluation in the three-component coupling reaction described
above. Our approach begins with ethyl (S)-pyroglutamate 23.
Thionation with Lawesson’s reagent was followed by Eschen-
moser sulfide contraction with 25 to give 26 in good overall
yield.25 Compound 26 was formed as a single double bond
isomer, assumed to be that shown,26 although we were unable
to observe any diagnostic NOE enhancements which would
confirm this assignment. Chemoselective reduction of the
aliphatic ester was followed by protection and de-acylation
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Scheme 9 Reagents and conditions: i, Lawesson’s reagent, toluene,
reflux, 1 h; ii, ethyl 2-bromoacetoacetate 25, CH2Cl2, NaHCO3, reflux,
16 h; iii, NaBH4, THF, reflux, 1 h; iv, TBSCl, imidazole, THF, 72 h;
v, NaOEt, EtOH, reflux, 2 h.
Scheme 11 Reagents and conditions: i, Si(NCS)4, CH3CHO, benzene,
3 h.
Scheme 10 Reagents and conditions: i, PhCONCS, benzene, 2 h.
deuterium exchange 1H-NMR data, which would have allowed
unambiguous assignment of structures, were not presented in
the original report. In the case of compound 32 the assigned
structure should be assumed to be correct. We have recently
prepared compound 34, and it shows a surprisingly broad peak
(which is more consistent in appearance with an NH proton)
for the alkene hydrogen at 6.45 ppm.29 The double bond
geometry in this compound is presently unknown, and may
indeed affect the chemical shifts.
The conditions of Kishi were used next, leading to the
high-yielding formation of a mixture of diastereoisomers
35 and 36 in a 2.3:1 ratio (Scheme 11). These isomers were
readily separated by flash column chromatography and
subjected to extensive NOE NMR studies. The minor isomer
36 shows a 1% NOE as shown in Fig. 2. While this is small,
there are no diagnostic enhancements shown by the major
isomer 35, so that on the basis of this, and precedent from our
previous work on alkenyloxazolines and alkenylthiazolines,24
we tentatively assign the stereochemistry of the two isomers
as shown.
Fig. 2 NOE enchancement for compound 36.
intermediate related to that shown in Scheme 7. If the inter-
mediate resembles that shown in Scheme 8, as originally
proposed by Kishi, the same major isomer would be expected
(vide supra), although clearly the extent of selectivity would
be difficult to predict. There is, however, another distinct possi-
bility for the lower diastereoselectivity. While a Z double bond
as in 37 would be expected to lead to isomer 35, the E double
bond isomer 38 would give, via a similar transition state, the
isomer 36.
Based on our previous work we might expect the formation
of isomer 35 exclusively under these conditions, since any
isomerisation of 35 into 36 would require elevated temper-
atures. However, this presumes a reaction proceeding via an
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Finally, conversion of the thiourea into the required guan-
idine was accomplished as shown in Scheme 12. Serendipitously,
the silyl protecting group was removed under these conditions,
presumably as a result of anchimeric assistance by the
neighbouring guanidine. The product 39 was isolated as the
formate salt after chromatography on silica gel, eluting with
CH2Cl2/MeOH/H2O/formic acid (85:14:0.5:0.5).1,15
4.15 (2H, q, J 7.1, CH2O), 4.05 (2H, q, J 7.1, CH2O), 2.95 (1H,
dd, J 17.0 and 4.6, one of CH C᎐O), 2.75 (1H, dd, J 17.0 and
᎐
2
4.6, one of CH C᎐O) and 1.15 (6H, m, 2 × CH ); δ (100 MHz;
᎐
2
3
C
CDCl ), 171.1 and 171.0 (ester C᎐O), 156.3 (carbamate C᎐O),
᎐
᎐
3
136.6 (aromatic C), 129.0, 128.6 and 128.5 (aromatic CH), 67.5
(Ph–CH2O), 62.3 (OCH2), 61.5 (OCH2), 50.8 (CHN), 37.2
(CH C᎐O), 14.5 and 14.4 (both OCH CH ); m/z (APCI) 324
᎐
2
2
3
(MHϩ, 100%).
Ethyl (3S )-3-[(benzyloxycarbonyl)amino]-4-hydroxybutanoate
(14)
Diethyl N-benzyloxycarbonyl-(S)-aspartate 13 (2.0 g, 6.2 mmol)
was dissolved in absolute ethanol (20 ml) and cooled to 0 ЊC.
Sodium borohydride (344 mg, 9.5 mmol) was added in portions
and the mixture stirred at 0 ЊC for 18 h. Ethyl acetate (50 ml)
was added and the organic layer was separated, washed with
brine (5 × 20 ml) and dried over MgSO4. The solvent was
removed in vacuo to give a pale oil which was purified by col-
umn chromatography (eluting with chloroform/ethyl acetate
1:1), late fractions yielding the title compound (575 mg, 33%) as
a clear oil which solidified on standing, mp 43–45 ЊC (lit.31
mp 44–46 ЊC); νmax (nujol)/cmϪ1 3233, 1730 and 1683; δH (400
MHz; CDCl3) 7.32–7.11 (5H, m, aromatic CH ), 5.46 (1H, d,
J 7.8, NH ), 5.26 (2H, s, PhCH2O), 4.16 (2H, q, J 7.1, OCH2),
4.08 (1H, m, CHN), 3.67 (2H, m, CH2OH), 2.56 (2H, m,
CH2CO2Et) and 1.25 (3H, t, J 7.1, CH2CH3); δC (100 MHz;
CDCl ) 170.7 (ester C᎐O), 156.4 (carbamate C᎐O), 135.2
Scheme 12 Reagents and conditions: i, CH3I, MeOH, reflux, 1 h then
NH4OAc, NH3, sealed tube, 80 ЊC, 48 h.
Conclusion
In summary, we have developed the three-component coupling
used by Kishi to prepare a bicyclic guanidine related to the
left-hand side of batzelladine A. This compound contains the
latent functionality for elaboration to give the tricyclic portion
of these natural products. The fully functionalised left-hand
side of batzelladine A will require removal of the hydroxy-
methyl directing group, which we envisage being accomplished
by oxidation to the aldehyde and deformylation.30 This
approach, and others, are currently under investigation and will
be reported in due course.
᎐
᎐
3
(aromatic C), 127.5, 127.2 and 127.1 (all aromatic CH), 65.9
(PhCH2O), 63.3 (OCH2), 59.9 (CH2OH), 48.7 (CHN), 34.9
(CH2CO2Et) and 13.1 (CH3).
Ethyl (3S )-3-[(benzyloxycarbonyl)amino]-4-(methylsulfonyl-
oxy)butanoate (15)
Experimental section
General experimental points
Ethyl (3S)-3-[(benzyloxycarbonyl)amino]-4-hydroxybutanoate
14 (230 mg, 0.85 mmol) was dissolved in dry CH2Cl2 (8 ml) and
cooled to 0 ЊC. Triethylamine (100 mg, 0.1 mmol) was added
and the mixture stirred for 10 min. Methanesulfonyl chloride
(77 mg, 0.87 mmol) was added and stirring continued at 0 ЊC
for 3 h. Having been washed with brine (20 ml) and dried over
MgSO4, the solvent was removed in vacuo to give the title
compound (250 mg, 82%) as a white solid, mp 50–52 ЊC; νmax
(nujol)/cmϪ1 3319, 1730, 1683 and 1158; δH (400 MHz; CDCl3)
7.32–7.11 (5H, m, aromatic CH ), 5.39 (1H, br-s, NH ), 5.04
(2H, s, OCH2Ph) 4.28 (3H, m, CH2OMs and CHN), 4.15 (2H,
q, J 7.1, OCH2), 2.92 (3H, s, CH3SO2), 2.60 (2H, m, CH2CO2Et)
and 1.21 (3H, t, J 7.1, OCH2CH3); δC (100 MHz; CDCl3) 171.0
(ester C᎐O), 156.0 (carbamate C᎐O), 136.5 (aromatic C), 129.0,
Melting points were determined on a Gallenkamp melting
point apparatus and are uncorrected. Infrared spectra were
recorded on a Perkin Elmer 1600 FTIR spectrophotometer.
Mass spectra were recorded on a Fisons VG Platform II
spectrometer. High-resolution mass spectra were performed at
the EPSRC centre for Mass Spectroscopy in Swansea. NMR
spectra were recorded on a Bruker DPX 400 spectrometer
operating at 400 MHz for 1H and at 100 MHz for 13C at 25 ЊC.
All chemical shifts are reported in ppm downfield from TMS.
Coupling constants (J) are reported in Hz. Multiplicity in
1H-NMR is reported as singlet (s), doublet (d), double doublet
(dd), double triplet (dt), double quartet (dq), triplet (t), and
multiplet (m). Multiplicity in 13C-NMR was obtained using the
DEPT pulse sequence. Flash chromatography was performed
using Matrex Silica 60 35–70 micron.
᎐
᎐
128.7 and 128.6 (all aromatic CH), 70.0 (CH2OMs), 67.5
(PhCH2O), 61.6 (OCH2), 52.9 (CH–N), 37.7 (CH3S), 35.5
(CH2CO2Et) and 14.5 (OCH2CH3); m/z (APCI) 360.3 (MHϩ,
70%), 174.3 (50) and 91.1 (100).
Diethyl N-benzyloxycarbonyl-(S )-aspartate (13)
Thionyl chloride (22 g, 282 mmol) was added to absolute
ethanol (200 ml) at 0 ЊC and stirred for 30 min. (S)-Aspartic
acid (21 g, 158 mmol) was added and the mixture heated under
reflux for 16 h. The solvent was removed in vacuo and the green
oil remaining was dissolved in saturated sodium carbonate
solution (200 ml) and cooled to 0 ЊC. Benzyl chloroformate
(28 g, 157 mmol) was added and the mixture stirred at rt for 2 h.
The reaction mixture was neutralised with 5 M HCl then
extracted with ethyl acetate (5 × 100 ml). The organic portions
were dried over MgSO4 and concentrated in vacuo. The residual
aromatic by-products were removed by vacuum distillation to
give a yellow oil, which solidified on standing to give a white
solid, recrystallisation of which from ethyl acetate/hexane gave
the title compound (48 g, 95%) as a white crystalline solid, mp
63–66 ЊC (lit.31 mp 64–66 ЊC); νmax (neat)/cmϪ1 1738, 1735 and
1693; δH (400 MHz; CDCl3) 7.25 (5H, m, aromatic CH ), 5.70
(1H, d, J 8.3, NH ), 5.05 (2H, s, PhCH2O), 4.50 (1H, m, CHN),
(4S )-4-[(Benzyloxycarbonyl)amino]-3,4-dihydro-5H-furan-2-one
(16)
Diethyl N-benzyloxycarbonyl-(S)-aspartate 13 (9.6 g, 29.7
mmol) was dissolved in absolute ethanol. Sodium borohydride
(1.6 g, 43.2 mmol) was added in portions and the mixture
stirred at 0 ЊC for 16 h. 5 M HCl (20 ml) was added slowly
followed by ethyl acetate (30 ml). The organic layer was
separated, washed with brine (5 × 20ml) and dried over MgSO4.
The solvent was removed in vacuo, and the yellow oil remaining
dissolved in ethyl acetate and heated under reflux for 2 h. The
solution remaining was concentrated in vacuo to give a white
solid, recrystallisation (ethyl acetate/chloroform/hexane) of
which yielded the title compound (5.46 g, 78%) as colourless
crystals, mp 100–104 ЊC (lit.32 mp 101–103 ЊC); νmax (nujol)/
cmϪ1 1778 and 1693; δH (400 MHz; CDCl3) 7.31–7.10 (5H, m,
aromatic CH ), 5.10 (1H, br-s, NH ), 5.04 (2H, s, PhCH2O),
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4.55–4.43 (2H, m, CH2O), 4.17 (1H, m, CHN), 2.78 (1H, dd,
J 17.8 and 7.3, CH C᎐O) and 2.40 (1H, dd, J 17.8 and 3.0,
2-Azido-3-(1,3-dithian-2-yl)propyl tert-butyl(dimethyl)silyl ether
(22a)
᎐
2
one of CH C᎐O); δ (100 MHz; CDCl ) 176.0 (lactone C᎐O),
᎐
᎐
2
C
3
2-Methanesulfonyloxy-3-(1,3-dithian-2-yl)propyl
tert-butyl-
156.3 (carbamate C᎐O), 136.4 (aromatic C), 129.0, 128.8 and
᎐
(dimethyl)silyl ether 21a (1 g, 2.6 mmol) was dissolved in dry
DMSO (5 ml). Sodium azide (400 mg, 6.1 mmol) was added
and the mixture heated in a sealed tube at 80 ЊC for 72 h.
Dichloromethane (20 ml) and water (20 ml) were added, the
organic layer was separated, washed with brine (10ml) and
water (10ml), dried over MgSO4, and concentrated in vacuo.
The brown oil remaining was purified by column chromato-
128.6 (aromatic CH), 74.1 (OCH2), 67.6 (PhCH2O), 48.4
(CHN) and 35.1 (CH C᎐O); m/z (APCI) 236 (MHϩ, 10%) and
᎐
2
91 (100).
1-(1,3-Dithian-2-yl)-1-ethanone (18)33
1,3-Dithiane 17 (3 g, 27 mmol) was dissolved in dry THF
(50 ml) and cooled to Ϫ40 ЊC under N2. n-Butyllithium (14 ml
of a 2.5 M solution in hexanes, 35.1 mmol) was added and the
miture stirred at Ϫ40 ЊC under N2 for 1 h. Dry ethyl acetate
(5.16 ml, 54 mmol) was added and the reaction mixture stirred
at Ϫ40 ЊC for 1 h, and allowed to warm to rt. Saturated
ammonium chloride solution (30 ml) and diethyl ether (30 ml)
were added. The organic layer was separated, washed with brine
(20 ml) dried over MgSO4, and concentrated in vacuo. The
resulting yellow oil was purified by column chromatography
(eluting with diethyl ether/petroleum ether 1:4), late fractions
yielding the title compound (2.0 g, 42%) as a clear oil; νmax
(neat)/cmϪ1 1708, 1422 and 1358; δH (400 MHz; CDCl3) 4.16
(1H, s, SCHS), 3.20 (2H, m, CH2S), 2.55 (2H, m, CH2S),
graphy (eluting with CH2Cl2), early fractions providing the title
compound (760 mg, 82%) as a yellow oil (Found: MNH4
ϩ
,
351.1696. C13H31N4OS2Si requires M, 351.1709); νmax (neat)/
cmϪ1 2928, 2125, 1253 and 1113; δH (400 MHz; CDCl3) 4.09
(1H, dd, J 9.2 and 5.4, SCHS), 3.67 (2H, m, one of CH2OSi
and CHN3), 3.56 (1H, dd, J 11.3 and 3.5, one of CH2OSi),
2.95–2.75 (4H, m, 2 × CH2S), 2.15 (1H, m, one of CH2CHN3),
1.85–1.68 (3H, m, one of CH2CHN3 and CH2CH2S), 0.80 [9H,
s, (CH3)3CSi], 0.00 (3H, s, CH3Si) and Ϫ0.03 (3H, s, CH3Si);
δC (100 MHz; CDCl3) 65.4 (CH2OSi), 59.8 (CHN3), 42.9
(SCHS), 35.3 (CH2CHN3), 29.3 (one of CH2S), 28.9 (one of
CH2S), 26.3 [(CH3)3CSi], 26.2 (CH2CH2S), 18.3 [(CH3)3CSi]
and 0.0 [(CH3)2Si]; m/z (CI) 351 (MNH4ϩ, 20%), 308 (79),
133 (100) and 119 (54).
2.24 (3H, s, CH C᎐O) and 2.02–1.89 (2H, m, CH CH S);
᎐
3
2
2
δ (100 MHz; CDCl ) 201.2 (C᎐O), 49.1 (SCHS), 28.0 (CH S),
᎐
C
3
2
2-Hydroxy-3-(1,3-dithian-2-yl)propyl benzyl ether (20b)36
27.0 (CH C᎐O) and 26.7 (CH CH S).
᎐
3
2
2
1,3-Dithiane 17 (1.48 g, 12 mmol) was dissolved in dry THF
(30 ml) and cooled to Ϫ40 ЊC. n-Butyllithium (6.4 ml of a 2.5 M
solution in hexane, 16 mmol) was added and the mixture stirred
under N2 for 1 h. Benzyl glycidyl ether 19b 37 (2 g, 12 mmol) was
added and the reaction mixture stirred for 1 h at Ϫ40 ЊC, then
allowed to warm to rt over 1 h. The solution was quenched with
saturated ammonium chloride solution (20 ml). Diethyl ether
(20 ml) was added and the organic layer was separated, washed
with brine (20 ml), dried over MgSO4, and concentrated
in vacuo. The yellow oil resulting was dissolved in CH2Cl2 and
filtered through a pad of silica. The filtrate was concentrated
in vacuo to give the title compound (2.3 g, 67%) as a yellow oil;
νmax (neat)/cmϪ1 3434, 2899 and 1115; δH (400 MHz; CDCl3)
7.32–7.11 (5H, m, aromatic CH ), 4.46 (1H, d, J 11.8, OCH2Ph),
4.42 (1H, d, J 11.8, OCH2Ph), 4.24 (1H, dd, J 9.6 and 4.9,
SCHS), 4.04 (1H, m, CHOH), 3.55 (1H, dd, J 10.0 and 3.8, one
of CH2OBn), 3.30 (1H, dd, J 10.0 and 6.6, one of CH2OBn),
2.89–2.72 (4H, m, 2 × CH2S), 2.05 (1H, m, one of CH2CHOH)
and 1.93–1.73 (3H, m, CH2CH2S and one of CH2CHOH);
δC (100 MHz; CDCl3) 138.2 (aromatic C), 128.9, 128.3 and
128.2 (aromatic CH), 74.4 (PhCH2O), 73.8 (CH2OBn), 67.6
(CHOH), 44.1 (SCHS), 39.3 (CH2CHOH), 30.8 and 30.4
(CH2S) and 26.3 (CH2CH2S); m/z (APCI) 285 (MHϩ, 100%),
177 (100) and 87 (75).
2-Hydroxy-3-(1,3-dithian-2-yl)propyl tert-butyl(dimethyl)silyl
ether (20a)34
1,3-Dithiane 17 (4.26 g, 34.6 mmol) was dissolved in dry THF
(40 ml), cooled to Ϫ40 ЊC, and stirred under N2 for 1 h. n-Butyl-
lithium (17.2 ml of a 2.5 M solution in hexane, 43 mmol) was
added and the mixture stirred for 1 h at Ϫ40 ЊC. tert-Butyl-
dimethylsilyloxy-2,3-epoxypropane 19a 35 (6.5 g, 33 mmol) in
dry THF (5 ml) was added with stirring under N2. The mixture
was stirred at Ϫ40 ЊC for 2 h and allowed to warm to rt. Water
(15 ml) and diethyl ether (20 ml) were added and the organic
layer separated, washed with brine, dried over MgSO4 and
concentrated in vacuo to yield the title compound (7.7 g, 76%)
as a clear oil; δH (400 MHz; CDCl3) 4.22 (1H, dd, J 9.7 and 4.8,
SCHS), 3.95 (1H, m, CHOH), 3.55 (1H, dd, J 9.7 and 3.7, one
of CH2OSi), 3.35 (1H, J 9.7 and 6.4, one of CH2OSi), 2.90–2.75
(4H, m, 2 × CH2S), 2.00 (1H, m, one of CH2CHOH), 1.90–1.70
(3H, m, CH2CH2S and one of CH2CHOH), 0.82 [9H, s,
(CH3)3Si] and Ϫ0.02 [6H, s, (CH3)2Si].
2-Methanesulfonyloxy-3-(1,3-dithian-2-yl)propyl tert-butyl-
(dimethyl)silyl ether (21a)
2-Hydroxy-3-(1,3-dithian-2-yl)propyl tert-butyl(dimethyl)silyl
ether 20a (4.6 g, 15 mmol) was dissolved in dry CH2Cl2 (20 ml)
and cooled to 0 ЊC. Triethylamine (2.16 ml, 16.5 mmol) and
methanesulfonyl chloride (1.28 ml, 16.5 mmol) were added and
the reaction mixture was stirred at 0 ЊC for 3 h. Water (40 ml)
was added and the organic layer was separated, washed with
brine (20ml), dried over MgSO4, and concentrated in vacuo.
The resulting brown oil was purified by column chromato-
graphy (eluting with CH2Cl2), early fractions yielding the title
compound (3.4 g, 58%) as a yellow oil; νmax (neat)/cmϪ1 2930,
1360 and 1173; δH (400 MHz; CDCl3) 4.83 (1H, m, CHOMs),
4.04 (1H, dd, J 9.3 and 5.3, SCHS), 3.71 (1H, dd, J 11.0 and 5.3,
one of CH2OSi), 3.65 (1H, dd, J 11.0 and 4.6, one of CH2OSi),
3.05 (3H, s, CH3SO2), 2.89–2.70 (4H, m, 2 × CH2S), 2.18–2.02
(3H, m, CH2CHOMs, and one of CH2CH2S), 1.81–1.66 (1H,
m, one of CH2CH2S), 0.80 [9H, s, (CH3)3CSi] and 0.02 [6H, s, 2
× (CH3)2Si]; δC (100 MHz; CDCl3) 80.3 (CHOMs), 65.2
(CH2OSi), 53.6 (CH3S), 43.2 (SCHS), 37.4 (CH2CHOMs),
30.4 and 30.0 (CH2S), 26.2 [(CH3)3CSi], 26.0 (CH2CH2S) and
18.5 [(CH3)3CSi] and Ϫ4.6 [(CH3)2Si].
2-Methanesulfonyloxy-3-(1,3-dithian-2-yl)propyl benzyl ether
(21b)
2-Hydroxy-3-(1,3-dithian-2-yl)propyl benzyl ether 20b (1.56 g,
5.3 mmol) was dissolved in dry CH2Cl2 (20 ml). Triethylamine
(0.76 ml, 5.3 mmol) was added and the mixture stirred at 0 ЊC
for 10 min. Methanesulfonyl chloride (0.43 ml, 4.3 mmol) was
then added and the mixture stirred for 0 ЊC for 3 h. Water
(10 ml) was added and the organic layer was separated, washed
with brine (20ml), dried over MgSO4 and concentrated in vacuo.
The brown oil resulting was purified by column chromato-
graphy (eluting with CH2Cl2), early fractions yielding the title
compound (1.55 g, 81%) as a clear oil (Found: MHϩ, 363.5416.
C15H23O4S3 requires M, 363.5413); νmax (neat)/cmϪ1 2819, 1354
and 1172; δC (400 MHz; CDCl3) 7.32–7.11 (5H, m, aromatic
CH ), 5.03 (1H, m, CHOMs), 4.50 (1H, d, J 11.9, one of
PhCH2O), 4.47 (1H, d, J 11.9, one of PhCH2O), 4.03 (1H, dd,
J 10.4 and 4.9, SCHS), 3.47 (2H, m, CH2OBn), 2.98 (3H, s,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 0 3 – 2 0 1 1
2008

View Article Online
CH3SO2), 2.80 (4H, m, 2 × CH2S), 2.22–2.10 (1H, ddd, J 14.2,
8.3 and 4.9, one of CH2CHOMs), 2.00 (2H, m, one of CH2-
CHOMs and one of CH2CH2S) and 1.90 (1H, m, CH2CH2S);
δC (100 MHz; CDCl3) 135.8 (aromatic C), 127.1, 126.5 and
126.4 (aromatic CH), 76.9 (CHOMs), 71.9 (PhCH2O), 69.8
(CH2OBn), 41.1 (SCHS), 37.2 (CH3SO2), 35.8 (CH2CHOMs),
28.5 and 28.2 (CH2S) and 24.2 (CH2CH2S); m/z (APCI) 363
(MHϩ, 100%) and 69 (70).
Ethyl 2-bromoacetoacetate (25)39
Ethyl acetoacetate (15 g, 0.11 mol) was dissolved in dry acetone
and cooled to 0 ЊC under N2. N-Bromosuccinimide (20 g,
0.11 mol) was added and the yellow solution stirred for 1 h.
After filtration, the mixture was concentrated in vacuo to give a
white residue which was washed with hexane (5 × 30 ml). The
combined hexane washings were washed with water (30 ml) and
dried over MgSO4. Concentration in vacuo gave the title
compound (15.9 g, 69%) a clear oil which was used without
further purification; νmax (neat)/cmϪ1 1728; δH (400 MHz;
CDCl3) 4.81 (1H, s, CHBr), 4.23 (2H, q, J 7.1, OCH2), 2.42
2-Azido-3-(1,3-dithian-2-yl)propyl benzyl ether (22b)
2-Methanesulfonyloxy-3-(1,3-dithian-2-yl)propyl benzyl ether
21b (500 mg, 1.38 mmol) was dissolved in DMSO (3 ml).
Sodium azide (449 mg, 7.0 mmol) was added and the solution
heated in a sealed tube at 80 ЊC for 72 h. Water (10 ml) and
CH2Cl2 (10 ml) were added and the organic layer was separated,
washed with water (5 × 10ml), dried over MgSO4, and concen-
trated in vacuo. The brown oil resulting was purified by column
chromatography (eluting with CH2Cl2) early fractions yielding
the title compound (310 mg, 75%) as a clear oil (Found: MHϩ,
310.1048. C14H20N3OS3 requires M, 310.1052); νmax (neat)/cmϪ1
2901, 2101, 1257 and 1112; δH (400 MHz; CDCl3) 7.32–7.10
(5H, m, aromatic CH ), 4.53 (1H, d, J 12.0, one of PhCH2O),
4.49 (1H, d, J 12.0, one of PhCH2O), 4.09 (1H, dd, J 7.9 and
6.4, SCHS), 3.86 (1H, m, CHN3), 3.55 (1H, dd, J 10.0 and
3.9, one of CH2OBn), 3.45 (1H, dd, J 10.0 and 7.0, one of
CH2OBn), 2.92–2.71 (4H, m, 2 × CH2S), 2.10 (1H, m one of
CH2CH2S) and 1.92–1.78 (3H, m, one of CH2CH2S and
CH2CHN3); δC (100 MHz; CDCl3) 138.0 (aromatic C), 128.9,
128.2 and 128.0 (aromatic CH), 73.7 (PhCH2O), 73.0
(CH2OBn), 58.7 (SCHS), 44.2 (CHN3), 36.9 (CH2CHN3), 30.7
and 30.3 (2 × CH2S) and 26.2 (CH2CH2S); m/z (APCI) 310
(MHϩ, 100%).
(3H, s, CH C᎐O) and 1.26 (3H, t, J 7.1, OCH CH ); δ (100
᎐
3
2
3
C
MHz, CDCl ) 191.0 (ketone C᎐O), 174.4 (ester C᎐O), 63.9
᎐
᎐
3
(OCH ), 49.6 (CHBr), 26.8 (CH C᎐O) and 14.2 (OCH CH ).
᎐
2
3
2
3
Ethyl (2S )-5-[(E )-1-(ethoxycarbonyl)-2-oxopropylidene]-3,4-di-
hydro-2H-pyrrole-2-carboxylate (26)26
Ethyl (2S)-5-thioxo-3,4-dihydro-5H-pyrrole-2-carboxylate 24
(1 g, 5.9 mmol) was dissolved in dry CH2Cl2 (30 ml). To the
stirred solution, sodium hydrogencarbonate (2.0 g, 24 mmol)
and ethyl 2-bromoacetoacetate 25 (2.45 g, 12 mmol) were added
and the mixture heated under reflux for 16 h under N2. The
green reaction mixture was filtered through Celite® and
concentrated in vacuo. The resulting green oil was purified by
column chromatography (eluting with hexane/ethyl acetate 4:1),
late fractions yielding the title compound (1.19 g, 71%) as a
yellow oil; νmax (neat)/cmϪ1 3219, 1745, 1690, 1642 and 1547;
δH (400 MHz; CDCl3) 11.72 (1H, br-s, NH ), 4.45 (1H, dd, J 9.0
and 5.5, CH–N), 4.20–4.10 (4H, m, 2 × OCH2), 3.20–3.05 (2H,
m, CH C᎐C), 2.35 (3H, s, CH C᎐O), 2.27 (1H, m, one of
᎐
᎐
3
2
CH2CHN), 2.10 (1H, m, one of CH2CHN) and 1.24 (6H, m,
2 × OCH2CH3); δC (100 MHz; CDCl ) 197.4 (ketone C᎐O),
᎐
3
172.8 (one of ester C᎐O), 169.8 (one of ester C᎐O), 167.4
᎐
᎐
Ethyl (S )-pyroglutamate (23)
(C᎐CN), 98.7 (C᎐CN), 68.9 (one of OCH ), 60.4 (CHN), 58.7
᎐
᎐
2
(S)-Glutamic acid (10 g, 68 mmol) was dissolved in absolute
ethanol (100 ml), and cooled to 0 ЊC. Thionyl chloride (10 ml,
136 mmol) was added dropwise, the mixture stirred for 30 min
at rt, and heated under reflux for 90 min. The clear solution
resulting was concentrated in vacuo to give a thick oil, which
was heated under aspirator vacuum at 130 ЊC for 1 h. The
viscous oil remaining solidified on standing to give a waxy
white solid which was distilled twice under reduced pressure
(Kugelrohr oven temp. 180 ЊC, 0.1 torr) to give the title
compound (7.0 g, 75%) as a clear oil that solidified on standing,
mp 49–50 ЊC (lit.38 mp 50–51 ЊC); νmax (neat)/cmϪ1 1735 and
1634; δH (400 MHz; CDCl3) 6.80 (1H, br-s, NH ), 4.25 (3H, m,
CH2O and CHN), 2.56–2.34 (3H, m, CH2CO, and one of CH2),
2.28–2.19 (1H, m, one of CH2) and 1.25 (3H, t, J 7.1,
(one of OCH ), 33.3 (CH C᎐C), 29.9 (CH C᎐O), 24.3
᎐
᎐
3
2
2
(CH2CHN), 13.4 (one of OCH2CH3) and 13.1 (OCH3CH3);
m/z (APCI) 270 (MHϩ, 100%).
Ethyl 2-[(5S )-5-(hydroxymethyl)-3,4-dihydro-2H-pyrrole-2-yl-
idene]-3-oxobutanoate (27)26
Ethyl (2S)-5-[(E)-1-(ethoxycarbonyl)-2-oxopropylidene]-3,4-
dihydro-2H-pyrrole-2-carboxylate 26 (1.35 g, 5.1 mmol) was
dissolved in THF (12 ml) and water (3 ml). Sodium borohydride
(1.87 g, 5.1 mmol) was added and the mixture heated under
reflux for 1 h. The THF was removed in vacuo and the remain-
ing aqueous residue was saturated with sodium chloride and
extracted with CH2Cl2 (4 × 10ml). The organic portions were
combined, dried over MgSO4, and concentrated in vacuo to
yield the title compound (1.08 g, 94%) as a yellow oil that was
used without further purification; νmax/cmϪ1 (neat) 3397, 1685
and 1595; δH (400 MHz; CDCl3) 11.60 (1H, br-s, NH ), 4.12
(2H, q, J 7.1, OCH2), 4.00 (1H, m, CH–N), 3.70 (1H, dd, J 11.4
and 4.5, one of CH2OH), 3.48 (1H, dd, J 11.4 and 7.1, one of
OCH2CH3); δC (100 MHz; CDCl ), 178.6 (ester C᎐O), 172.4
᎐
3
(lactam C᎐O), 62.1 (CH –O), 55.9 (CH-N), 29.7 (CH –CO),
᎐
2
2
25.6 (CH2) and 14.5 (CH3); m/z (APCI) 158 (MHϩ, 100%).
Ethyl (2S )-5-thioxo-3,4-dihydro-5H-pyrrole-2-carboxylate (24)
Ethyl (S)-pyroglutamate 23 (1.14 g, 7.3 mmol) was dissolved in
dry toluene (15 ml). To the stirred solution, Lawesson’s reagent
(1.6 g, 4.0 mmol) was added in one portion and the mixture
heated under reflux under N2 for 1 h. The dark mixture result-
ing was concentrated under reduced pressure to give a dark
residue which was purified by column chromatography (eluting
with hexane/ethyl acetate 5:1), late fractions affording the title
compound (1.15g, 92%) as a yellow oil that crystallised on
standing, mp 67–69 ЊC (lit.26 mp 67–68 ЊC); νmax (neat)/cmϪ1
3307, 2980, 1737, 1505 and 1212; δH (400 MHz; CDCl3) 7.85
(1H br-s, NH ), 4.45 (1H, dd, J 8.5 and 6.5, CHN), 4.15 (2H, q,
CH OH), 3.13 (1H, ddd, J 15.6, 9.4 and 5.9, one of CH C᎐C),
᎐
2
2
3.06 (1H, ddd, J 15.6, 9.5 and 6.1, one of CH C᎐C), 2.25 (3H, s,
᎐
2
CH C᎐O), 2.03 (1H, m, one of CH CHN) and 1.73 (1H, m, one
᎐
3
2
of CH2CHN) and 1.35 (3H, t, J 7.1, OCH2CH3); δC (100 MHz;
CDCl ) 188.8 (ketone C᎐O), 174.9 (ester C᎐O), 169.2 (C᎐CN),
᎐
᎐
᎐
3
99.4 (C᎐CN), 65.3 (OCH ), 62.9 (CHN), 60.0 (CH OH), 35.5
᎐
2
2
(CH C᎐C), 31.0 (CH C᎐O), 23.3 (CH2CHN) and 14.8
᎐
᎐
3
2
(CH2CH3); m/z (APCI) 228 (MHϩ, 100%).
Ethyl 2-[(5S )-5-(tert-butyl(dimethyl)siloxymethyl)-3,4-dihydro-
2H-pyrrole-2-ylidene]-3-oxobutanoate (28)
J 7.1, OCH ), 2.99–2.82 (2H, m, CH C᎐S), 2.58–2.45 (1H, m,
᎐
2
2
one of CH2CHN), 2.35–2.20 (1H, m, one of CH2CHN) and
1.25 (3H, t, J 7.1, CH3); δC (100 MHz; CDCl ) 207.4 (C᎐S),
Ethyl 2-[(5S)-5-(hydroxymethyl)-3,4-dihydro-2H-pyrrole-2-yl-
idene]-3-oxobutanoate 27 (1.35 g, 3.96 mmol) in dry THF
(10 ml) was added to a stirred solution of chloro-t-butyl-
dimethylsilane (595 mg, 3.96 mmol) and imidazole (280 mg,
᎐
3
170.6 (C᎐O), 63.1 (CHN), 62.5 (OCH ), 43.1 (CH C᎐S), 27.4
᎐
᎐
2
2
(CH2CHN) and 14.5 (CH3).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 0 3 – 2 0 1 1
2009

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4.05 mmol) in dry THF (10 ml). The reaction mixture was
stirred at room temperature for 72 h. Water (10 ml) and diethyl
ether (10 ml) were added, and the organic layer was separated,
dried over MgSO4, and concentrated in vacuo to yield the title
compound (1.05g, 65%) as a clear oil that was used without
further purification; νmax (neat)/cmϪ1 1689, 1601 and 1544;
δH (400 MHz; CDCl3) 12.45 (1H, br-s, NH ), 4.15 (2H, q, J 7.1,
OCH2), 3.94 (1H, m, CHN), 3.61 (1H, dd, J 10.3 and 4.1, one
of CH2OSi), 3.44 (1H, dd, J 10.3 and 6.4, one of CH2OSi), 3.17
132.3, 128.8 and 127.8 (all aromatic CH), 101.5 (C᎐CN), 63.7
᎐
(OCH ), 63.2 (CHN), 60.8 (CH OSi), 33.7 (CH C᎐C), 25.8
᎐
2
2
2
[(CH3)3CSi], 23.6 (CH2CHN), 18.2 [(CH3)3CSi], 14.3
(OCH2CH3), Ϫ5.3 and Ϫ5.4 (both CH3Si); m/z (APCI) 463
(MHϩ, 100%).
Ethyl 7-(tert-butyl(dimethyl)siloxymethyl)-3-methyl-1-thioxo-
1,2,3,5,6,7-hexahydropyrrolo[1,2-c]pyrimidine-4-carboxylate
(35 and 36)
(1H, ddd, J 15.9, 9.6 and 6.3, one of CH C᎐C), 3.05 (1H, ddd,
᎐
2
Silicon tetraisothiocyanate (700 mg, 2.7 mmol) was suspended
in dry benzene (10 ml). Acetaldehyde (110 mg, 2.7 mmol) was
added and the mixture stirred for 20 min at rt under N2. Ethyl
2-[(5S)-5-(tert-butyl(dimethyl)siloxymethyl)-3,4-dihydro-2H-
pyrrole-2-ylidene]acetate 29 (800 mg, 2.7 mmol) in dry benzene
(5 ml) was added and the mixture stirred at rt under N2 for
a further 3 h, then concentrated in vacuo to give the title
compound as a 2:1 mixture of diastereoisomers which were
separated by column chromatography (eluting with hexane/
ethyl acetate 9:1).
J 15.9, 9.6 and 6.2, one of CH C᎐C), 2.30 (3H, s, CH C᎐O),
᎐
᎐
3
2
2.00 (1H, m, one of CH2CHN), 1.72 (1H, m, CH2CHN), 1.21
(3H, t, J 7.1, OCH2CH3), 0.80 [9H, s, (CH3)3CSi], 0.06 (3H, s,
one of SiCH3) and 0.01 (3H, s, one of SiCH3); δC (100 MHz;
CDCl ) 196.7 (ketone C᎐O), 173.0 (ester C᎐O), 167.8 (C᎐CN),
᎐
᎐
᎐
3
97.7 (C᎐CN), 65.0 (OCH ), 61.9 (CHN), 58.6 (CH OSi),
᎐
2
2
37.6 (CH C᎐C), 33.5 (CH C᎐O), 28.4 (CH CHN), 25.8
᎐
᎐
2
3
2
[(CH3)3CSi], 20.8 (OCH2CH3), 17.1 [(CH3)3CSi], Ϫ2.8 and
Ϫ2.9 (both CH3Si); m/z (APCI) 342 (MHϩ, 100%).
Ethyl 2-[(5S )-5-(tert-butyl(dimethyl)siloxymethyl)-3,4-dihydro-
2H-pyrrole-2-ylidene]acetate (29)
Major isomer (35)
Clear gum (556 mg, 54%) (Found: MHϩ, 385.1978.
C18H33N2O3SSi requires M, 385.1981); νmax (neat)/cmϪ1 3390,
1686, 1649 and 1264; δH (400 MHz; CDCl3) 6.91 (1H, br-s,
NH ), 4.59 (1H, m, CHN), 4.30 (1H, q, J 6.0, CHCH3), 4.15
(1H, dd, J 10.5 and 4.5, one of CH2OSi), 4.00 (2H, m, OCH2),
3.75 (1H, dd, J 10.5 and 3.3, one of CH2OSi), 3.15 (1H, appar-
Sodium metal (98 mg, 4.3 mmol) was added to absolute ethanol
(10ml) and allowed to dissolve over 30 min. Ethyl 2-[(5S)-5-
(tert-butyl(dimethyl)siloxymethyl)-3,4-dihydro-2H-pyrrole-2-
ylidene]-3-oxobutanoate 28 (1.42 g, 4.3 mmol) in absolute
ethanol (5 ml) was added and the mixture heated under reflux
for 2 h. The ethanol was removed in vacuo, and the resulting
residue was dissolved in chloroform (20 ml), washed with satur-
ated sodium carbonate solution (10 ml), dried over MgSO4, and
the solvent removed in vacuo. The brown oil remaining was
purified by column chromatography (eluting with hexane/ethyl
acetate 3:1), early fractions affording the title compound (680
mg, 55%) as a yellow oil (Found: MHϩ, 299.2346. C15H29NO3Si
requires M, 299.2342); νmax (neat)/cmϪ1 3396 and 1715; δH (400
MHz; CDCl3) 7.95 (1H, br-s, NH ), 4.47 (1H, s, alkene CH ),
4.05 (2H, q, J 7.1, OCH2), 3.85 (1H, m, CHN), 3.55 (1H, dd,
J 10.1 and 3.8, one of CH2OSi), 3.49 (1H, dd, J 10.1 and 6.5,
ent dd, J 9.1 and 8.4, one of CH C᎐C), 3.05 (1H, m, one of
᎐
2
CH C᎐C), 2.10–1.89 (2H, m, CH CHN), 1.24 (3H, d, J 6.0,
᎐
2
2
CHCH3), 1.19 (3H, t, J 7.1, OCH2CH3), 0.77 [9H, s,
(CH3)3CSi], 0.07 (3H, s, one of CH3Si) and 0.00 (3H, s, one of
CH Si); δ (100 MHz; CDCl ) 173.6 (C᎐S), 164.6 (C᎐O), 149.4
᎐
᎐
3
C
3
(C᎐CN), 99.6 (C᎐CN), 62.9 (CHN), 61.9 (OCH ), 59.0
᎐
᎐
2
(CH OSi), 47.2 (CHCH ), 30.8 (CH C᎐C), 24.7 [(CH ) CSi],
᎐
2
3
2
3 3
24.2 (CH2CHN), 24.1 (CHCH3), 16.1 [(CH3)3CSi], 13.4
(OCH2CH3), 0.0 (CH3Si) and Ϫ4.6 (CH3Si); m/z (APCI) 385
(MHϩ, 100%).
one of CH OSi), 2.65–2.48 (2H, m, CH C᎐CH), 1.95 (1H, m,
᎐
2
2
Minor isomer (36)
one of CH2CHN), 1.75 (1H, m, one of CH2CHN), 1.24 (3H, t,
J 7.1, CH3), 0.85 [9H, s, (CH3)3CSi], 0.05 (3H, s, one of CH3Si)
and 0.00 (3H, s, one of CH3Si); δC (100 MHz; CDCl3) 170.9
Clear gum (240 mg, 23%) (Found: MHϩ, 385.1982.
C18H23N2O3SSi requires M, 385.1981); νmax (neat)/cmϪ1 3390,
1686, 1649 and 1264; δH (400 MHz; CDCl3) 7.01 (1H, br-s,
NH ), 4.93 (1H, m, CHN), 4.35 (1H, m, CHCH3), 4.15 (2H, q, J
7.1, OCH2), 4.06 (1H, dd, J 10.4 and 3.6, one of CH2OSi), 3.67
(1H, dd, J 10.4 and 2.3, one of CH2OSi), 3.20 (1H, m, one of
(C᎐O), 166.2 (C᎐CN), 77.1 (alkene CH), 66.9 (OCH CH ),
᎐
᎐
2
3
61.5 (CHN), 58.8 (CH OSi), 32.0 (CH C᎐CH), 26.1 [(CH ) -
᎐
2
2
3 3
CSi], 24.6 (CH2CHN), 18.7 [(CH)3CSi], 15.1 (OCH2CH3),
Ϫ4.4 and Ϫ4.5 (both CH3Si); m/z (APCI) 300 (MHϩ, 100%).
CH C᎐C), 3.05 (1H, m, one of CH C᎐C), 2.01 (2H, m,
᎐
᎐
2
2
Ethyl 3-(benzoylamino)-2-{(5S )-5-(tert-butyl(dimethyl)siloxy-
methyl)-3,4-dihydro-2H-pyrrole-2-ylidene}-3-thioxopropanoate
(30)
CH2CHN), 1.20 (3H, t, J 7.1, OCH2CH3), 1.18 (3H, d, J 6.3,
CH3CH), 0.85 [9H, s, (CH3)3CSi], 0.06 (3H, s, one of CH3Si)
and 0.00 (3H, s, one of CH Si); δ (100 MHz; CDCl ) 174.2 (C᎐
᎐
3
C
3
S), 164.5 (C᎐O), 149.9 (C᎐CN), 100.1 (C᎐CN), 63.3 (OCH ),
᎐
᎐
᎐
2
Ethyl 2-[(5S)-5-(tert-butyl(dimethyl)siloxymethyl)-3,4-dihydro-
2H-pyrrole-2-ylidene]acetate 29 (100 mg, 0.34 mmol) was
dissolved in dry benzene (7 ml). Benzoylisothiocyanate (55 mg,
0.34 mmol) was added and the yellow mixture stirred under N2
at rt for 2 h. The yellow solution resulting was concentrated in
vacuo and purified by column chromatography (eluting with
CH2Cl2/diethyl ether 5:1). Early fractions yielded the title
compound (56 mg, 36%) as a yellow solid, mp 128–130 ЊC; νmax
(neat)/cmϪ1 3432, 2927, 1702, 1603, 1517 and 1214; δH (400
63.0 (CHN), 59.9 (CH OSi), 46.7 (CHCH ), 30.6 (CH C᎐C),
᎐
2
2
3
24.8 [(CH3)3CSi], 22.7 (CH2CHN), 22.2 (CH3CH), 17.0
[(CH3)3CSi], 13.4 (OCH2CH3) and 0.00 [(CH3)2Si]; m/z (APCI)
385 (MHϩ, 100%).
Ethyl (3R,7S )-7-(hydroxymethyl)-3-methyl-1-imino-1,2,3,5,6,7-
hexahydropyrrolo[1,2-c]pyrimidine-4-carboxylate formic acid
salt (39)
MHz; CDCl ), 13.85 (1H, br-s, S᎐CNHC᎐O), 12.71 (1H, br-s,
Ethyl (3R,7S)-7-(tert-butyl(dimethyl)siloxymethyl)-3-methyl-1-
thioxo-1,2,3,5,6,7-hexahydropyrrolo[1,2-c]pyrimidine-4-carb-
oxylate 35 (130 mg, 0.34 mmol) was dissolved in dry methanol
(5 ml). Iodomethane (23 µl, 0.35 mmol) was added and the
solution heated under reflux for 1 h. The volatiles were removed
in vacuo and the residue redissolved in dry methanol (2 ml).
Ammonium acetate (140 mg, 1.8 mmol) was added, and gas-
eous ammonia bubbled through the solution for 10 min. The
solution was then heated in a sealed tube at 80 ЊC for 48 h. The
solution was loaded directly onto a silica column and eluted
᎐
᎐
3
NH ), 7.94 (2H, d, J 7.1, aromatic CH ), 7.59 (1H, t, J 7.1,
aromatic CH ), 7.44 (2H, t, J 7.1, aromatic CH ), 4.16 (3H, m,
OCH2 and CHN), 3.73 (1H, dd, J 11.3 and 4.0, one of
CH2OSi), 3.51 (1H, dd, J 11.3 and 7.0, one of CH2OSi), 3.30
(1H, m, one of CH C᎐C), 3.14 (1H, m, one of CH C᎐C), 2.10
᎐
᎐
2
2
(1H, m, one of CH2CHN), 1.72 (1H, m, one of CH2CHN), 1.20
(3H, t, J 7.1, OCH2CH3), 0.84 [9H, s, (CH3)3CSi], 0.02 (3H, s,
one of CH3Si) and 0.00 (3H, s, one of CH3Si); δC (100 MHz;
CDCl ) 174.5 (ester C᎐O), 164.8 (C᎐CN), 134.8 (aromatic C),
᎐
᎐
3
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 0 3 – 2 0 1 1
2010

View Article Online
187; K. Nagasawa, H. Koshino and T. Nakata, Tetrahedron Lett.,
2001, 42, 4155; K. Nagasawa, A. Georgieva, H. Koshino, T. Nakata,
T. Kita and Y. Hashimoto, Org. Lett., 2002, 4, 177.
with CH2Cl2/MeOH/HCO2H/H2O (85:14:0.5:0.5), late fractions
yielding the title compound (74 mg, 73%) as a clear gum;
δH (400 MHz; CDCl3) 8.40 (1H, br-s, NH ), 8.00–7.70 (2H, br-s,
NH2), 4.45 (1H, q, J 6.1, CHCH3), 4.38 (1H, m, CHN), 4.15
(2H, m, OCH2), 3.81 (1H, dd, J 11.8 and 3.1, one of OCH2),
3.75 (1H, dd, J 11.8 and 2.6, one of CH2OH), 3.31 (1H, appar-
15 S. G. Duron and D. Y. Gin, Org. Lett., 2001, 3, 1551.
16 J. Shimokawa, K. Shirai, A. Tanatani, Y. Hashimoto and
K. Nagasawa, Angew. Chem., Int. Ed., 2004, 43, 1559.
17 For a review, see: M. C. Elliott, E. Kruiswijk and M. S. Long,
Tetrahedron, 2001, 57, 6651.
ent dd, J 17.9 and 8.2, one of CH C᎐C), 2.80 (1H, m, one of
᎐
2
18 M. C. Elliott and E. Kruiswijk, Chem. Commun., 1997, 2311;
M. C. Elliott, D. E. Hibbs, D. S. Hughes, M. B. Hursthouse,
E. Kruiswijk and K. M. A. Malik, J. Chem. Crystallogr., 1998, 28,
663; M. C. Elliott and E. Kruiswijk, J. Chem. Soc., Perkin Trans. 1,
1999, 3157.
CH C᎐C), 2.19–2.01 (1H, m, one of CH CHN), 2.04–1.94 (1H,
᎐
2
2
m, one of CH2CHN), 1.37 (3H, d, J 6.1, CHCH3) and 1.19 (3H,
t, J 7.1, OCH2CH3); δC (100 MHz; CDCl ) 165.0 (ester C᎐O),
᎐
3
151.1 (C᎐NH), 150.9 (NC᎐C), 102.5 (C᎐CN), 62.8 (CHN), 61.8
᎐
᎐
᎐
(OCH ), 59.0 (OCH ), 46.3 (CHCH ), 29.9 (CH C᎐C), 20.5
19 Alkenyloxazolines such as 7 undergo double addition of isocyanates
᎐
2
2
2
3
as shown in Scheme 1. In contrast, the corresponding thiazolines
(CH3CH), 23.2 (CH2CHN) and 13.9 (OCH2CH3); m/z (APCI)
254 (cation Mϩ, 100 %).
only give single addition, although
a further equivalent of
isocyanate can be added under more forcing conditions. The
reaction with a chloroformate would be directly analogous to this:
M. C. Elliott, A. E. Monk, E. Kruiswijk, D. E. Hibbs, R. L. Jenkins
and D. V. Jones, Synlett., 1999, 1379.
Acknowledgements
20 V. Skaric and J. Matulic-Adamic, J. Chem. Soc., Perkin Trans. 1,
1985, 779; Y. H. Kim and H. R. Kim, Heterocycles, 1986, 24, 3023;
A. W.-Y. Chan and B. Ganem, Tetrahedron Lett., 1995, 36, 811.
21 Part of this work has been published in preliminary form:
M. C. Elliott and M. S. Long, Tetrahedron Lett., 2002, 43, 9191.
22 H. Taguchi, H. Yazawa, J. F. Arnett and Y. Kishi, Tetrahedron Lett.,
1977, 18, 627; H. Tanino, T. Nakata, T. Kaneko and Y. Kishi, J. Am.
Chem. Soc., 1977, 99, 2818; Y. Kishi, Heterocycles, 1980, 14, 1477.
23 C. Y. Hong and Y. Kishi, J. Am. Chem. Soc., 1992, 114, 7001.
24 M. C. Elliott, E. Kruiswijk and D. J. Willock, Tetrahedron Lett.,
1998, 39, 8911; M. C. Elliott, E. Kruijwijk and D. J. Willock,
Tetrahedron, 2001, 57, 10139.
25 A more direct route would involve Eschenmoser sulfide contraction
with ethyl 2-bromoacetate. However, we found this to be low-
yielding and capricious, such that the present route was the most
efficient.
26 M. D. Bachi, R. Breiman and H. Meshulam, J. Org. Chem., 1983,
48, 1439.
27 H. Bahaji, P. Bastide, J. Bastide, C. Rubat and P. Tronche,
Eur. J. Med. Chem., 1988, 23, 193.
28 For representative examples, see: M. P. Moyer, P. L. Feldman and
H. Rapoport, J. Org. Chem., 1985, 50, 5223; P. Brunerie,
J.-P. Célérier, H. Petit and G. Lhommet, J. Heterocycl. Chem., 1986,
23, 1183; H. K. Lee, J. Kim and C. S. Pak, Tetrahedron Lett., 1999,
40, 2173.
29 M. C. Elliott and S. V. Wordingham, unpublished results.
30 For a related used of this reaction, see: M. Ikeda, Y. Kugo,
Y. Kondo, T. Yamazaki and T. Sato, J. Chem. Soc., Perkin Trans. 1,
1997, 3339.
We are indebted to the EPSRC for funding (GR/L53687), and
to Cardiff University for additional support. We would also like
to acknowledge the contribution of Craig Phillips to the early
stages of this project, and the EPSRC Mass Spectrometry
centre for provision of high-resolution mass spectrometric data.
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 0 3 – 2 0 1 1
2011