Intramolecular Aldol Ring Closures of Cysteine Derivatives Leading to Densely Functionalised Pyroglutamates

Article abstract of DOI:10.1055/s-0037-1611829

The synthesis of densely functionalised pyroglutamates derived from cysteine by an aldol cyclisation strategy has been achieved.

Full text of DOI:10.1055/s-0037-1611829

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
Synlett
H. Almahli et al.
Letter
Intramolecular Aldol Ring Closures of Cysteine Derivatives Leading
to Densely Functionalised Pyroglutamates
Hadia Almahli
R2
OH
R3
Niamh C. Jimenez
Mark G. Moloney*
O
O
CO2Me
R2
NaOMe, MeOH
13 examples
CO2Me
N
O
N
R3
S
The Department of Chemistry, Chemistry Research Laboratory,
The University of Oxford, 12 Mansfield Road, Oxford OX1 3TA,
UK
R1
S
R1
R1 = t-Bu, i-Pr, Ph, o-FC H , o-CF C H ; R2 = H, MeO, CH =CHCH -, p-BrC H ; R3 = H, Me
6
4
3
6
4
2
2
6 4
mark.moloney@chem.ox.ac.uk
Oxford Suzhou Centre for Advanced Research, Building A, 388
Ruo Shui Road, Suzhou Industrial Park, Jiangsu, 215123, P. R. of
China
Received: 08.03.2019
Accepted after revision: 26.04.2019
Published online: 13.05.2019
extended to thiazolidines other than those derived from
pivaldehyde, since such systems exhibited unexpected be-
haviour in related Dieckmann cyclisations. This report de-
1
DOI: 10.1055/s-0037-1611829; Art ID: st-2019-d0141-l
tails our results in that regard.
The starting thiazolidines 4a–e were obtained by heat-
ing cysteine to reflux with the respective aldehyde under
Abstract The synthesis of densely functionalised pyroglutamates de-
rived from cysteine by an aldol cyclisation strategy has been achieved.
1
reported conditions (Scheme 2 and Table 1); these were
Key words aldol reaction, cyclization, heterocycles, pyroglutamate,
lactams
obtained in good to excellent yield, as a mixture of insepa-
rable diastereomers usually favouring the cis-isomer. A sim-
ilar outcome was observed earlier with analogous cysteine
derivatives.1
We have reported that malonyloxazolidines and malo-
nylthiazolidines derived from serine and threonine, or cys-
teine, respectively, are suitable for highly chemoselective
Dieckmann ring closures, and that the serine- and thre-
onine-derived oxazolidine systems 1 are, moreover, suit-
able for diastereoselective aldol ring closures after conver-
sion into their ketoamide derivatives 2,
functionalised pyroglutamates 3 (Scheme 1), which are
closely related to the lactam moiety of oxazolomycin. Re-
lated aldol ring closures have been reported and it has
been suggested that such processes are biomimetic.11 Of in-
terest to us was the possibility that a similar ring closure
might also be applicable to cysteine-derived systems, even
though these aldol reactions may be reversible and the
five-membered ring containing the large sulfur atom might
be expected to influence the outcome of such a reaction.
Moreover, of interest was whether the reaction might be
1–3
Table 1 Yields of Thiazolidines 4a–e
Compound R1
H for H-2 (ppm)
Ratio (cis/trans) Yield (%)
4–6
giving highly
4
a
t-Bu
i-Pr
4.45
4.35
5.57
5.79
5.86
4.52
4.43
5.82
6.01
6.10
1:0.4
2.5:1
1:0.7
1:1
89
80
7
8,9
4b
4c
4d
10
Ph
100
61
o-FC
o-CF
6
H
4
4
e
3
C
6
H
4
1:0.53
17
12
Initial preparation of the required side chain -ketoacids
from Meldrum’s acid, by acylation and then acid-catalysed
collapse, using reported methodology, gave ketoacids 5
X
R2
R1
R1
OH
CO2Me
R1
MeO2C
HN
MeO2C
R
CO2Me
OH
2
(
i)
(ii)
(iii)
-
+
O
N
O
O
Cl H3N
N
R1 = H or Me
X
R1
O
t-Bu
O
O
t-Bu
t-Bu
1
2
3
7
Scheme 1 Previously reported preparation of highly functionalised pyroglutamates 3. Reagents and conditions: (i) Me CCHO, petrol (40/60), reflux,
3
2
1
6–20 h; (ii) XCH C(O)CH(R )CO H, DCCI, DMAP; (iii) KOt-Bu, t-BuOH.
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
Synlett
H. Almahli et al.
Letter
R2
R2
MeO2C
CO Me
OH
CO Me
O
O
2
OH
CO2Me
SH
R2
(i)
(ii)
(iii)
7
7a
7
7a
CO2Me
2
Cl-H3N+
HN
S
N
2
+
O
O
N
N
1
S
1
R1
R1
3
3
S
S
R1
R1
4
a–e
a only (iv)
CO2Me
6a–m
7
a–m (major)
8a–m (minor)
4
R
Me
OH
O
O
7
CO2Me
(iii)
R
7a
N
O
N
1
S
3
Me
S
t-Bu
t-Bu
1
1
0a R = MeO
0b R = PhS
11a R = MeO (76%)
11b R = PhS (76%)
1
Scheme 2 Preparation of malonamides 10 and pyroglutamates 7, 8 and 11. Reagents and conditions: (i) R CHO, petrol (40/60), reflux, 16–20 h; (ii)
2
R CH C(O)CH CO H 5, DCCI, DMAP; (iii) NaOMe, MeOH, r.t., 24 h; (iv) RCH C(O)CH(Me)CO H 9, DCCI, DMAP.
2
2
2
2
2
(
Scheme 2);5,6 coupling of these with thiazolidines 4a–e
gave acetoacetylthiazolidines 6a–m in good yield (Scheme
azolidines 6a–m are not separated, and since their aldol
closure leads to enantiomers of each of the products 7 and
8, the overall process proceeds with some loss of enantio-
meric integrity. The stereochemistry of the newly created
stereogenic centre for the major diastereomer was estab-
lished as 7R (that is, hydroxyl group endo) by NOE analysis
(Figure 1), and the stereochemistry of the others was as-
sumed by the similarity of chemical shift values of H-6exo
and H-6endo with this NOE-assigned structure (H-6 = 3.04
and 2.45 ppm for 7a). This was similar to reported chemical
2
and Table 2). These compounds existed as rotamers in
1
several cases, as evidenced by broad signals in the H NMR
spectrum, as keto-enol mixtures, and as a mixture of dia-
stereomers, leading to complex NMR spectra, but were
nonetheless used directly for further reaction. As has been
observed previously, the diastereomeric ratio of the start-
ing thiazolidines 4a–e is not necessarily translated into that
for the acetoacetylthiazolidines 6a–m due to equilibration
during the acylation process. When subjected to base
treatment (NaOMe), the acetoacetylthiazolidines 6a–m
gave the corresponding aldol adducts usually as diastereo-
1
shifts of the H-6 protons for the serine (H-6
( = 3.2
endo
4
3
ppm) and H-6exo ( = 2.5 ppm) ) and threonine (H-6 ( =
exo
6
3.1 ppm) and H-6endo ( = 2.4 ppm) ). This earlier work had
meric mixtures of 7a–m and 8a–m in good overall yield
shown those chemical shifts were conserved in similar di-
astereomers, generally regardless of substitution, and in the
systems reported here, the chemical shift values for H-1
(
Scheme 2 and Table 2);13 however, as has been shown pre-
1
viously in a related system, cis- and trans-acetoacetylthi-
Table 2 Yields of Products 6–8
6
, 7 or 8
R1
R2
6
7 and 8
H
 for H-3
Yield (%)a
Ratio
cis/trans
Yield (%)
Ratio
7R-7/7S-8
Major
Minor
a
b
c
d
e
f
t-Bu
H
48
44
78
73
48
49
81
71
26
52
50
46
47
1:1
1:2
1:1
1:1
1:1
1:0.6
2:3
1:1
4:1
2:3
7:3
0:1
0:1
88
69
99
100
41
52
48
96
76
71
80
79
82
1:0.4
1:0.3
1:0a
5.11
5.05
5.11
5.08
4.86
6.17
5.99
6.36
6.28
6.33
6.43
6.22
6.20
5.07
4.97
–
t-Bu
t-Bu
t-Bu
i-Pr
MeO
CH =CHCH
2
2
p-BrC
MeO
H
6
H
4
1:0a
–
1:0.3
1:0.3
1:0a
4.79
6.24
–
Ph
g
h
i
Ph
p-BrC
H
6
H
4
o-FC
o-FC
o-FC
o-FC
o-CF
o-CF
6
6
6
6
3
3
H
H
H
H
4
4
4
4
1:0.2
1:0.4
1:0a
6.29
6.25
–
MeO
j
CH
2
=CHCH
2
2
k
l
p-BrC
6
H
4
1:0a
–
C
6
6
H
4
4
H
1:0.2
1:0 a
6.26
–
m
C
H
2
CH =CHCH
a
Single diastereomer isolated only.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
Synlett
H. Almahli et al.
Letter
OMe
OH
CO2Me
C6H4Br
OH
H Me
Me
HO
OH
CO2Me
OH
Me
CO Me
H
H
7
7
7
7
7a
CO Me
7
7a
H
7
7a
CO Me
7a
2
2
2
a
O
H
O
H
N
O
1
H
O
H
O
N
1
1
N 3
N 3
1
N
1
3
3
3
H
S
H
H
H
S
S
S
S
t-Bu
H
Ph
H
Ph
H
Ph
H
7a
7e
7f
8f
7g
Figure 1
and H-6 were also conserved across multiple substitution
patterns, with the differences of chemical shift of each
geminal set being smaller for the major isomer (Δ = 0.5
and 0.1 ppm, respectively) than for the minor isomer (Δ =
Funding Information
A.H. gratefully acknowledges the award of a Council for At-Risk Aca-
demics (CARA) Fellowship and Christ Church College, University of
Oxford, and N.J. acknowledges funding from EPSRC SBM CDT.()
0.8 and 0.5 ppm, respectively). The yields of these aldol re-
actions were often significantly better than those obtained
5,7
6
Supporting Information
in our earlier work with serine and threonine; the 7R di-
astereoselectivity, however, was poorer than this earlier
work, presumably arising from the need to accommodate
the larger sulfur in the bicyclic system. Of interest is that
enantioselective aldol reactions of malonic acid half thio-
esters with aldehydes have recently been reported.14
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611829.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
References
An examination of more substituted systems was made,
and to this end, malonamides 10a–b were prepared from
the corresponding carboxylic acid 9 and thiazolidine 4a, by
(
1) Panduwawala, T. D.; Iqbal, S.; Tirfoin, R.; Moloney, M. G. Org.
Biomol. Chem. 2016, 14, 4464.
6
(
2) (a) Anwar, M.; Moloney, M. G. Chem. Biol. Drug Des. 2013, 81,
645. (b) Anwar, M.; Cowley, A. R.; Moloney, M. G. Tetrahedron:
Asymmetry 2010, 21, 1758. (c) Anwar, M.; Moloney, M. G. Tetra-
hedron Lett. 2007, 48, 7259.
DCC coupling (Scheme 2). Aldol reaction using base
(NaOMe) gave the corresponding pyroglutamates 11a–b in
good yield as single diastereomers, the stereochemistry of
which was assigned on the basis of the chemical shift infor-
mation outlined above; thus, the H-1 geminal set showed a
difference of Δ = 0.5 and 0.1 ppm, corresponding to the 7R
(
3) Andrews, M. D.; Brewster, A. G.; Crapnell, K. M.; Ibbett, A. J.;
Jones, T.; Moloney, M. G.; Prout, K.; Watkin, D. J. Chem. Soc.,
Perkin Trans. 1 1998, 223.
(4) Andrews, M. D.; Brewster, A. G.; Moloney, M. G. Synlett 1996,
(
endo-hydroxyl) configuration, in keeping with that ob-
612.
served in the simpler systems, and in close correspondence
(5) Angelov, P.; Chau, Y. K. S.; Fryer, P. J.; Moloney, M. G.;
Thompson, A. L.; Trippier, P. C. Org. Biomol. Chem. 2012, 10,
3472.
4,5
to equivalent reported analogues in the serine and thre-
6
onine series.
(
6) Heaviside, E. A.; Moloney, M. G.; Thompson, A. L. RSC Adv. 2014,
, 16233.
Assay of these compounds against a small panel of Gram
positive (Methicillin resistant Staphylococcus aureus, Strep-
tococcus pneumonia) and Gram negative (Escherichia coli
4
(7) Andrews, M. D.; Brewster, A. G.; Moloney, M. G. J. Chem. Soc.,
Perkin Trans. 1 2002, 80.
(EC 34), Klebsiella pneumonia (KL 18) and Pseudomonas
(8) Ishihara, J.; Hatakeyama, S. Chem. Rec. 2014, 14, 663.
(9) Moloney, M. G.; Trippier, P. C.; Yaqoob, M.; Wang, Z. Curr. Drug
Discovery Technol. 2004, 1, 181.
aeruginosa (PS 23)) bacteria mostly showed no activity,
confirming earlier results that simple lactam systems do
not display such activity and which only becomes observ-
(
10) (a) Satoh, N.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2011, 13,
3028. (b) Nguyen, H.; Ma, G.; Gladysheva, T.; Fremgen, T.; Romo,
15
able with further suitable ring substitution. The exception
was 6p, which showed good activity against both Methicil-
lin resistant Staphylococcus aureus and Streptococcus pneu-
monia, with an MIC of 3.9 g/mL.
D. J. Org. Chem. 2011, 76, 2. (c) Nguyen, H.; Maz, G.; Romo, D.
Chem. Commun. 2010, 46, 4803.
(
11) Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007, 9, 2143.
(12) Moloney, M. G.; Yaqoob, M. Tetrahedron Lett. 2008, 49, 6202.
(13) Method for aldol cyclisation: To a solution of N-acylated thi-
azolidine (1.0 equiv) in methanol was added sodium methoxide
In conclusion, we have shown that aldol reactions may
be achieved in sterically encumbered thiazolidine sub-
strates derived from cysteine, and that these may proceed
in a diastereoselective manner, at least in some cases. This
outcome offers the prospect of the construction of sulfur-
containing mimics of the oxazolomycin group of natural
(1.05 equiv) and the resulting mixture was stirred at r.t. for 15–
2
4 h. Subsequently, the mixture was partitioned between Et O
2
and 1 M HCl. The Et O layer was washed with brine, dried
2
(
MgSO ), filtered and concentrated in vacuo to furnish the crude
4
pyroglutamates.
Methyl (3R,7R,7aR)
9,16
products.
and
(3R,7S,7aR)-3-(tert-butyl)-7-
hydroxy-7-methyl-5-oxodihydro-1H,3H-pyrrolo[1,2-c]thi-
azole-7a(5H)-carboxylate (7a and 8a). Yellow oil. IR: 2958,
–
1 1
1739, 1688, 1616, 1366, 1260, 1108, 1022 cm
. H NMR (500
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
Synlett
H. Almahli et al.
Letter
MHz, CDCl ):  (major) = 5.11 (s, 1 H, H-3), 3.80 (s, 3 H, CO Me),
[]D23 –19.8 (c 1.0 in CHCl ). IR: 3358, 2930, 2854, 1713,
3
2
3
–1 1
3
(
3
(
.62 (d, J = 12.1 Hz, 1 H, H-1), 3.55 (d, J = 12.1 Hz, 1 H, H-1), 3.04
d, J = 16.3 Hz, 1 H, H-6), 2.45 (d, J = 16.3 Hz, 1 H, H-6), 1.27 (s,
H, H-9), 0.93 (s, 9 H, t-Bu);  (minor) = 5.07 (s, 1 H, H-3), 3.82
s, 3 H, CO Me), 3.69 (d, J = 12.9 Hz, 1 H, H-1), 3.27 (d, J =
1583 cm . H (500 MHz, CDCl ):  = 7.19–7.23 (m, 5 H, ArH),
3
5.11 (s, 1 H, C(3)H), 3.79 (s, 3 H, OCH ), 3.75 (d, J = 16.2 Hz, 1 H,
3
C(1)H H ), 3.65 (d, J = 16.2 Hz, 1 H, C(1)H H ), 3.22 (d, J =
A
B
A
B
16.2 Hz, 1 H, CH H ), 3.10 (q, J = 7.2 Hz, 1 H, C(6)H), 3.07 (d, J =
2
A B
13
1
1
2.9 Hz, 1 H, H-1), 3.23 (d, J = 15.7 Hz, 1 H, H-6), 2.42 (d, J =
5.6 Hz, 1 H, H-6), 1.51 (s, 3 H, H-9), 0.93 (s, 9 H, t-Bu). C NMR
16.2 Hz, 1 H, CH H ), 1.07 (d, 3 H, CH ), 0.93 (s, 9 H, t-Bu).
C
A
B
3
13
(126 MHz, CDCl ):  = 176.7 (C(O)), 172.1 (CO Me), 126.8–129.4
3
2
(
500 MHz, CDCl ):  (major) = 175.3 (C-5), 172.0 (CO Me), 85.0
(C(Ar)), 83.50 (C(7a)), 83.31 (C(3)), 72.85 (C(7)), 53.43 (OMe),
3
2
(
C-7a), 79.6 (C-7), 73.1 (C-3), 53.1 (CO Me), 47.2 (C-6), 38.3 (C-
0), 33.4 (C-1), 26.4 (t-Bu), 21.8 (C-9);  (minor) = 173.6 (C-5),
51.46 (OMe), 46.49 (C(6)), 41.11 (CH ), 38.40 (C(3)), 34.32
2
2
+
1
1
4
(C(CH ) ), 26.64 (C(CH ) ), 14.41 (CH ). HRMS (ESI): m/z [M ]
3
3
3
3
3
72.4 (CO Me), 84.2 (C-7a), 78.7 (C-7), 72.2 (C-3), 53.0 (CO Me),
calcd for C20H28NO S : 410.14543; found: 410.14539.
2
2
4 2
6.7 (C-6), 38.3 (C-10), 33.8 (C-1), 26.4 (t-Bu), 24.04 (C-9).
(14) Wang, Y.; Huang, G.; Hu, S.; Jin, K.; Wu, Y.; Chen, F. Tetrahedron
2017, 73,34 5055.
+
+
+
HRMS (ESI ): m/z [M + H ] calcd for C13H22NO S : 288.12641;
4
found 288.12650.
(15) Jeong, Y.-C.; Moloney, M. G. Synlett 2009, 2487.
(16) Eto, K.; Yoshino, M.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.
Org. Lett. 2011, 13,19 5398.
Methyl
(3R,7S,7aR)-3-(tert-butyl)-7-hydroxy-6-methyl-5-
oxo-7-((phenylthio)methyl)-hexahydropyrrolo[1,2-c]thi-
azole-7a(5H)-carboxylate (11b). Yield: 0.19 g (76%); yellow oil;
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D