Bicyclic Lactams Derived from Serine or Cysteine and 2-Methylpropanal

Article abstract of DOI:10.1055/s-0039-1691569

Bicyclic lactams may be prepared from serine or cysteine and 2-methylpropanal; the resulting S, N -heterocycles are more stable than the corresponding O, N -heterocycles but both are synthetic intermediates capable of further elaboration.

Full text of DOI:10.1055/s-0039-1691569

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
en
H. Bagum et al.
Letter
Synlett
Bicyclic Lactams Derived from Serine or Cysteine and 2-Methyl-
propanal
Halima Baguma
OH
R
O
O
CO2Me
KOt-Bu, THF
reflux, 8 h
Bethany R. Shirea
Kirsten E. Christensena
Miroslav Genovc
Alexander Pretschc
Dagmar Pretschc
Z
6
7
EtO
N
O
N
4
R
X
2
X = O, S
Z = H, CO2Me
R = H, Me
X
5 examples, 13–76%
Mark G. Moloney*a,b
a The Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, 12 Mansfield Road, Oxford. OX1 3TA, UK
mark.moloney@chem.ox.ac.uk
b Oxford Suzhou Centre for Advanced Research, Building A, 388
Ruo Shui Road, Suzhou Industrial Park, Jiangsu, 215123, P. R. of
China
c Oxford Antibiotic Group, The Oxford Science Park, Magdalen
Centre, Oxford OX4 4GA, UK
Received: 05.12.2019
Accepted after revision: 27.12.2019
Published online: 21.01.2020
ty of similar variation for the O,N-heterocycle system was
less certain. The feasibility of preparing and using such te-
tramates has been investigated and is reported here.
DOI: 10.1055/s-0039-1691569; Art ID: st-2019-d0655-l
Methyl ester hydrochlorides of the amino acids L-serine
and L-cysteine 1a and 1b were treated with 2-methylpro-
panal/triethylamine following Seebach’s protocol (Scheme
2)7 to furnish oxazolidine 4a and thiazolidine 4b as mix-
tures of diastereomers, which were used directly without
purification; the preference of the latter for the cis-2,5 dia-
stereomer results from ring-chain tautomerism giving the
more stable isomer.5,8,9 DCC mediated coupling gave
malonamides 5a,b and subsequent Dieckmann cyclisation
afforded the novel methyl ester tetramates 6a (14%) or 6b
(47%);10 the relative stereochemistry of key intermediates
being established by NOE analysis (Figure 1). It is evident
that the isopropyl group is capable of directing a similar
chemical outcome to that of the t-butyl group,8,11 although
this comes with complication in the NMR spectrum as a re-
sult of the non-symmetrical nature of the isopropyl system.
In the case of the thiazolidine system, bicyclic tetramate 6b
was obtained along with decarboxylated 6c as an insepara-
ble mixture. Tetramates 6a,b were readily converted into
mesylates 7a,b in 14 and 64% yield, respectively;10 the sig-
nificantly better yields in the case of the latter again reflect
Abstract Bicyclic lactams may be prepared from serine or cysteine
and 2-methylpropanal; the resulting S,N-heterocycles are more stable
than the corresponding O,N-heterocycles but both are synthetic inter-
mediates capable of further elaboration.
Key words lactams, antibiotics, cyclisation, heterocycles
We have shown that L-serine, L-cysteine, L-allothreonine
and L-threonine methyl esters 1a–d may be converted into
their corresponding O,N- or S,N-heterocycles 2a–d by reac-
tion with pivaldehyde, and that these in turn may be con-
verted into tetramates 3a–d by a highly chemo- and enantio-
selective Dieckmann cyclisation using the reported proto-
cols (Scheme 1).1–3 The t-butyl group acts simultaneously
as a protecting and chemoselective directing group, princi-
pally from its bulk. One disadvantage of this process is the
expense and sometimes limited availability of pivaldehyde,
and the question arose whether 2-methylpropanal might
provide an alternative. Although the use of other aldehydes
and especially benzaldehydes has been shown for cysteine,4
where the S,N-heterocycles are more stable,5,6 the possibili-
O
CO2Me
EtOC(O)CH2CO2H
DCC, DMAP, DCM
t-BuCHO, Et3N
Petrol, 110 °C, 16 h
CO2Me
XH
R2 R1
6
CO2Me
R2
R1
R2
7
H
4
N
–Cl +H3N
O
N
R1
2
4
KOt-Bu, THF
reflux, 8 h
X
2
X
t-Bu
t-Bu
1a R1 = H, R2 = H, X = O
1b R1 = Me, R2 = H, X = O
1c R1 = H, R2 = Me, X = O
1d R1 = H, R2 = H, X = S
2a R1 = H, R2 = H, X = O
2b R1 = Me, R2 = H, X = O
2c R1 = H, R2 = Me, X = O
2d R1 = H, R2 = H, X = S
3a R1 = H, R2 = H, X = O
3b R1 = Me, R2 = H, X = O
3c R1 = H, R2 = Me, X = O
3d R1 = H, R2 = H, X = S
Scheme 1
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H. Bagum et al.
Letter
Synlett
OH
R
CO2Me
EtOC(O)CH2CO2H
O
O
CO2Me
X
CO2Me
KOt-Bu, THF
reflux, 8 h
Z
H
7
6
i-PrCHO
4
N
EtO
N
DCC, DMAP, DCM
O
–Cl +H3N
N
2
4
R
X
Et3N, Petrol
110 °C, 16 h
2
X
XH
5a R = H, X = O
5b R = H, X = S (74%)
5c R = Me, X = S (81%)
1a X = O
1b X = S
4a X = O
4b X = S (76%)
6a R = H, X = O, Z = CO2Me
6b R = H, X = S, Z = CO2Me (47%)
6c R = H, X = S, Z = H
6d R = Me, X = S, Z = CO2Me (76%)
6e R = Me, X = S, Z = H (13%)
MsCl
DIPEA
Z = CO2Me
ArB(O)H)2
PdCl2(dppb)
Na2CO3, toluene
EtOH
Ar
Ar
CO2Me
R
OMs
Z
TFA
R
C6H4p-OMe
CO2Me
HSCH2CH2CH2SH
CF3CH2OH
CO2Me
H2, PtO2
EtOAc, RT
7
6
6
7
6
7
reflux
O
O
4
N
N
O
4
N
4
2
O
2
N
See Table 1
2
O
X
See Table 1
Ar = MeOC6H4 only
X
H
HO
10 (97%)
9ai Ar = MeOC6H4
9aii Ar = Ph
9aiii Ar = ClC6H4
8a R = H, X = O
8b R = H, X = S
8c R = Me, X = S
7a R = H, X = O, Z = CO2Me (14%)
7b R = H, X = S, Z = CO2Me (64%)
7c R = H, X = S, Z = H
7d R = Me, X = S, Z = CO2Me (61%)
7e R = Me, X = S, Z = H (13%)
TFA
ArB(O)H)2
PdCl2(dppb)
Na2CO3, toluene
EtOH
Ar = Ph
HSCH2CH2CH2SH
CF3CH2OH
OMs
Me
C6H4p-OMe
H
Me
H
7
6
7
6
Ph
CO2Me
O
O
reflux
N
N
4
4
2
2
S
S
O
N
H
HO
11 (97%)
7e
12 (32%)
Scheme 2
the better stability to acid (and therefore chromatography)
of the S,N-system over the O,N-system. However, for the ox-
azolidine system, difficulties with purification, thought to
arise from the greater acid sensitivity of this system, meant
that crude material needed to be taken forward to form the
mesylate 7a, which could readily be isolated in pure form.
CO2Me
CO2Me
CO2Me
CO2Me
H
H
H
H
H
H
Me
O
H
HN
S
EtO2C
N
S
EtO2C
HN
S
N
S
H
H
H
H
O
i-Pr
5c
OMs
4b’
4b
5b
Me
OH
CO2Me
OH
CO2Me
OMs
CO2Me
Me
Me
OMs
H
OMs
CO2Me
H
CO2Me
H
H
O
O
H
H
H
O
O
O
O
N
N
N
N
N
N
H
H
H
H
H
H
S
S
S
O
S
S
H
H
H
H
H
H
6d
7a
6b
7b
7d
7e
OMe
H
Cl
H
H
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
H
O
O
H
H
H
O
N
N
N
H
H
O
O
O
H
H
H
9aiii
9ai
9aii
Figure 1 NOE analysis of selected compounds.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
H. Bagum et al.
Letter
Synlett
Table 1 Suzuki Coupling of 7a,b with Arylboronic Acids and Hydrogenation of 8ai–aiii
Compound
Ar
4-MeOC6H4
Reaction time (h)
Product
Yield (%)
Reaction time (h) Product
Yield (%)
7a
6
6
8ai
47
45
40
72
74
41
13
12
11
6
5
6
–
–
–
–
–
–
9ai
9aii
9aiii
–
82
75
85
–
C6H5
8aii
8aiii
8bi
4-ClC6H4
4-MeOC6H4
C6H5
3
7b
7c
3
3
8bii
8biii
8ci
–
–
4-ClC6H4
4-MeOC6H4
C6H5
5
–
–
24
20
24
–
–
8cii
8ciii
–
–
4-ClC6H4
–
–
With mesylates 7a,b in hand, Suzuki coupling with 1.5
equivalent of aryl boronic acid resulted in the formation of
pyrrolinone derivatives 8ai–iii and 8bi–iii (Table 1).10 The
structures of 8aii and 8bii were further confirmed by single
crystal X-ray diffractrometry (Figure 2).12
showed the presence of rotameric exchange. Dieckmann
cyclisation under basic conditions resulted in inseparable
C7-methyl tetramates 6d and 6e.10 The stereochemistry of
the major tetramic acid 6d was determined by NOE analysis
(Figure 1). Treatment of this mixture with MsCl/DIPEA gave
mesylates 7d and 7e in 61% and 13% isolated yield, respec-
tively.10 The stereochemistry of both mesylates 7d and 7e
were confirmed by NOE analysis (Figure 1), and Suzuki cou-
pling with arylboronic acids furnished the desired coupling
adducts 8ci–iii and 12 (Scheme 2 and Table 1).10 However,
the reaction was much slower in this case and probably re-
flects the greater steric bulk in this system.
Broth assay of some of these compounds (8ai–aiii, 8bi–
biii, 8ci–8ciii) against Gram-positive (methicillin-resistant
Staphylococcus aureus) and Gram-negative (Escherichia coli
(EC 34)) bacteria showed no activity, confirming earlier re-
sults seen with related pyroglutamate derivatives.14
In conclusion, we have shown that bicyclic lactams may
be prepared from serine or cysteine and 2-methylpropanal;
the resulting S,N-heterocycles are more stable than the cor-
responding O,N-heterocycles but both are synthetic inter-
mediates capable of further elaboration. This approach
neatly complements earlier work leading to C-6 and C-7
functionalisation in related bicyclic systems.15
Treatment of pyrrolinones 8ai–iii with H2/PtO2 fur-
nished acid derivatives 9ai–iii in high yields (Table 1) and,
notably, the isolation of these products by flash column
chromatography was straightforward. Their stereochemis-
try was assigned by NOE analysis, which, in all cases,
showed strong relative enhancements between endo-H4-
H2 and endo-H7-H6 (Figure 1) and this was further con-
firmed by the X-ray crystal structure of 9aii (Figure 2).12
Representative compounds 8aii and 9ai were subjected to
N,O-acetal deprotection using the Corey–Reichard proto-
col13 and gave the pyroglutaminols 10 and 11 in excellent
yields (Scheme 2). The easier deprotection of the isopropyl
system over the t-butyl system is noteworthy, and again re-
flects their increased acid lability.1
This approach could also be extended by N-acylation of
thiazolidine 4b with ethyl -methylmalonyl chloride and
pyridine to furnish cis-2,5 malonamide 5c (Scheme 2),
found as a mixture of C7 epimers with 7R as the major iso-
mer (NOE, Figure 1), and 1D gradient NMR spectroscopy
8bii
8aii
9aii
Figure 2 Single-crystal X-ray crystal structures of 8aii, 8bii, 9aii.12 Displacement ellipsoids are drawn at 50% probability.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
H. Bagum et al.
Letter
Synlett
Funding Information
furnished pure mesylates 7d and 7e. Yield: 61% (1.82 g); colour-
25
less oil; Rf (40% EtOAc in Petrol) 0.37; []D +235.0 (c 1.0 in
CH2Cl2). IR: 2960 (C-H), 2935 (C-H), 1747 (C=O), 1713 (C=O) cm–1
.
H.B. gratefully acknowledges the award of a Scholarship from the
Commonwealth Scholarship Commission.
1H NMR (400 MHz, CDCl3):  = 0.87 (d, J = 6.6 Hz, 3 H, CH(CH3)),
1.02 (d, J = 6.6 Hz, 3 H, CH(CH3)), 1.78–1.84 (m, 1 H, CH(CH3)2),
1.85 (s, 3 H, C(7)CH3), 2.84 (d, J = 11.1 Hz, 1 H, C(4)HAHB), 3.23
(s, 3 H, OSO2CH3), 3.58 (d, J = 11.1 Hz, 1 H, C(4)HAHB), 3.76 (s,
3 H, CO2CH3), 4.70 (s, J = 9.7 Hz, 1 H, C(2)H). 13C NMR (100 MHz,
CDCl3):  = 8.6 (C(7)CH3), 19.6, 20.2 (CH(CH3)2), 35.2 (C(4)), 36.9
(CH(CH3)2), 39.5 (OSO2CH3), 53.7 (CO2CH3), 66.8 (C(2)), 78.2
(C(5)), 124.0 (C(7)), 154.0 (CO2CH3), 168.4 (C(8)), 171.4 (C(6)).
MS (ESI+): m/z (%) = 372.0 (100, [M + Na]+); HRMS (ESI+): m/z [M
+ Na]+ calcd for C13H19NNaO6S2: 372.0546; found: 372.0547.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691569.
Su
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References
Suzuki coupling:17
A
mixture of 1,4-bis(diphenylphos-
(1) Bagum, H.; Christensen, K. E.; Genov, M.; Pretsch, A.; Pretsch, D.;
Moloney, M. G. J. Org. Chem. 2019, 84, 10257.
(2) (a) Bagum, H.; Christensen, K. E.; Pretsch, A.; Genov, M.; Pretsch,
D.; Moloney, M. G. Tetrahedron 2019, 75, 130561. (b) Josa-
Cullere, L.; Moloney, M. G.; Thompson, A. L. Synlett 2016, 27,
1677.
(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) (a) Panduwawala, T. D.; Iqbal, S.; Tirfoin, R.; Moloney, M. G. Org.
Biomol. Chem. 2016, 14, 4464. (b) Panduwawala, T. D.; Josa-
Cullere, L.; Kuprov, I.; Odell, B.; Moloney, M. G.; Claridge, T. D.
W. J. Org. Chem. 2016, 81,10 4142.
phino)butane (0.06 equiv) and bis(benzonitrile)palladium(II)
chloride (0.05 equiv) in anhydrous toluene was stirred at room
temperature under a nitrogen atmosphere for 30 minutes to
form
a creamy orange slurry of [1,4-bis(diphenylphos-
phino)butane]palladium(II) chloride. Mesylate (1.0 equiv),
boronic acid (1.05–1.8 equiv), ethanol (7.0 equiv), 1 M aqueous
sodium carbonate solution (9–18 equiv) and anhydrous toluene
were added to the catalyst and the mixture was heated at reflux
for 3–30 hours. After cooling, water was added, and the mixture
was diluted with ethyl acetate. The aqueous phase was sepa-
rated and extracted with ethyl acetate. The combined organic
phases were dried, filtered and evaporated in vacuo to furnish
the crude product, which was then purified by flash column
chromatography.
(5) Lazar, L.; Fulop, F. Eur. J. Org. Chem. 2003, 3025.
(6) (a) Lazar, L.; Goblyos, A.; Martinek, T. A.; Fulop, F. J. Org. Chem.
2002, 67,14 4734. (b) Fulop, F.; Mattinen, J.; Pihlaja, K. Tetrahe-
dron 1990, 46, 6545. (c) Fulop, F.; Pihlaja, K.; Mattinen, J.;
Bernath, G. J. Org. Chem. 1987, 52, 3821.
(7) Seebach, D.; Aebi, J. D. Tetrahedron Lett. 1984, 25, 2545.
(8) Jeong, Y.-C.; Anwar, M.; Nguyen, T. M.; Tan, B. S. W.; Chai, C. L.
L.; Moloney, M. G. Org. Biomol. Chem. 2011, 9, 6663.
Typical reaction: Mesylate 7a (210 mg, 0.66 mmol) was reacted
with 4-methoxyphenylboronic acid (150 mg, 0.98 mmol),
PdCl2(dppb), and 1 M aqueous Na2CO3 solution (0.62 mL, 5.94
mmol) in ethanol (0.27 mL, 4.62 mmol) and toluene (12 mL) for
6 h. PdCl2(dppb) was prepared from (C6H5)2P(CH2)4P(C6H5)2
(16.9 mg, 0.04 mmol) and (C6H5CN)2PdCl2 (12.6 mg, 0.022
mmol) in toluene (2 mL). Yield: 47% (102 mg); yellow solid; mp
(9) Fulop, F.; Pihlaja, K.; Neuvonen, K.; Bernath, G.; Argay, G.;
Kalman, A. J. Org. Chem. 1993, 58, 1967.
25
90–92 °C; Rf (30% EtOAc in petrol): 0.25; []D +138.9 (c 1.0 in
CH2Cl2). IR: 2954 (C-H), 2868 (C-H), 1743 (C=O), 1712 (C=O) cm–1
.
(10) Dieckmann Cyclisation:3 To a solution of N-acyl oxazolidine or
thiazolidine 5a,b (1.0 equiv) in anhydrous THF was added
potassium tert-butoxide (1.05 equiv). The mixture was heated
at reflux for 3 h. The reaction mixture was partitioned between
Et2O and water, the aqueous phase was acidified with 2 M
aqueous HCl and the mixture was extracted with EtOAc. The
organic layer was washed with a 1 M aqueous solution of
NaH2PO4 and brine, dried over anhydrous Na2SO4 filtered and
concentrated under reduced pressure to give the methyl ester
tetramic acids 6a–e.
1H NMR (400 MHz, CDCl3):  = 0.91 (dd, J = 8.9, 6.8 Hz, 6 H,
HC(CH3)2), 1.80 (dq, J = 6.8, 5.6 Hz, 1 H, (HC(CH3)2), 3.48 (d, J =
8.3 Hz, 1 H, C(4)HAHB), 3.59 (s, 3 H, CO2CH3), 3.77 (s, 3 H, OCH3),
4.84 (d, J = 5.6 Hz, 1 H, C(2)H), 5.02 (d, J = 8.3 Hz, 1 H, C(4)HAHB),
6.19 (s, 1 H, C(7)H), 6.86 (d, J = 8.9 Hz, 2 H, C(3′)H), 7.31 (d, J =
8.9 Hz, 2 H, C(2′)H). 13C NMR (100 MHz, CDCl3):  = 17.1, 17.1
(HC(CH3)2), 33.2 (HC(CH3)2), 53.3 (CO2CH3), 55.5 (OCH3), 70.3
(C(4)), 76.8 (C(5)), 93.5 (C(2)), 114.7 (C(3′)), 119.0 (C(7)), 122.5
(C(1′)), 128.8 (C(2′)), 159.3 (C(6)), 161.9 (C(4′)), 170.1 (CO2CH3),
177.5 (C(8)). MS (ESI+): m/z (%) = 332.1 (30, [M + H]+); HRMS
([ESI]+): m/z [M + H]+ calcd for C18H22NO5: 332.1493; found:
332.1493.
Synthesis of Mesylate:16 Tetramic acid 6a–e (1.0 quiv) was dis-
solved in CH2Cl2 under a nitrogen atmosphere. Methanesulfonyl
chloride (1 equiv) and DIPEA (2 equiv) were added to this solu-
tion. The resulting mixture was stirred for 2–6 h at room tem-
perature until total consumption of the starting material. The
reaction mixture was washed with 5% HCl, 5% NaHCO3, and
brine, dried over MgSO4, and filtered. The solvent was removed
in vacuo and the residue was purified by chromatography on
silica gel using ethyl acetate/petroleum ether as eluants to give
pure mesylates 7a,c
(11) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem. Int. Ed.
Engl. 1996, 35, 2708.
(12) Low-temperature single-crystal X-ray diffraction data were col-
lected with a (Rigaku) Oxford Diffraction SuperNova diffrac-
tometer. Raw frame data were reduced using CrysAlisPro and
the structures were solved using ‘Superflip’.18 before refine-
ment with CRYSTALS19 as per the Supporting Information (CIF).
CCDC 1961419, 1961420, 1961421 contain the supplementary
crystallographic data for this paper. The data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/getstructures.
Representative reaction: Tetramic acids (6d + 6e, 2.32 g, 8.55
mmol) was reacted with MsCl (0.66 mL, 8.55 mmol) and DIPEA
(2.9 mL, 17.1 mmol) in CH2Cl2 (85 mL). Purification by flash
column chromatography (20–30% EtOAc in petroleum ether)
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

E
H. Bagum et al.
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(13) Corey, E. J.; Reichard, G. A. J. Am. Chem. Soc. 1992, 114, 10677.
(14) Jeong, Y.-C.; Moloney, M. G. Synlett 2009, 2487.
(16) Li, W.-R.; Lin, S. T.; Hsu, N.-M.; Chern, M.-S. J. Org. Chem. 2002,
67, 4702.
(15) (a) Dyer, J.; Keeling, S.; King, A.; Moloney, M. G. J. Chem. Soc.,
Perkin Trans. 1 2000, 2793. (b) Bailey, J. H.; Cherry, D. T.;
Crapnell, K. M.; Moloney, M. G.; Shim, S. B.; Bamford, M.;
Lamont, R. B. Tetrahedron 1997, 53, 11731.
(17) Jones, K.; Keenan, M.; Hibbert, F. A. Synlett 1996, 509.
(18) Palatinus, L.; Chapuis, G. J. Appl. Crystallogr. 2007, 40, 786.
(19) (a) Parois, P.; Cooper, R. I.; Thompson, A. L. Chem. Cent. J. 2015,
9, 1. (b) Cooper, R. I.; Thompson, A. L.; Watkin, D. J. J. Appl. Crys-
tallogr. 2010, 43, 1100.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E