Highly functionalised monocyclic and bicyclic β-lactams via alkene metathesis

Article abstract of DOI:10.1039/a607308e

Both monocyclic and bicyclic β-lactam systems are prepared via alkene metathesis reactions using Mo(=CHCPhMe₂)-(=NC₆H₃Pr(i)₂0[(OCMe(CF₃)₂]₂ or Ru(=CHPh)Cl₂(PCy₃

Full text of DOI:10.1039/a607308e

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Highly functionalised monocyclic and bicyclic b-lactams via alkene metathesis
Anthony G. M. Barrett,*a Simon P. D. Baugh,a Vernon C. Gibson,*a Matthew R. Giles,a Edward L. Marshalla
and Panayiotis A. Procopioub
a Department of Chemistry, Imperial College of Science, Technology and Medicine, London, UK SW7 2AY
b Department of Medicinal Chemistry, Glaxo Wellcome Research and Development Ltd, Gunnels Wood Road, Stevenage,
Hertfordshire, UK SG1 2NY
Both monocyclic and bicyclic b-lactam systems are prepared
via alkene metathesis reactions using Mo(NCHCPhMe2)-
(NNC6H3Pri2)[(OCMe(CF3)2]2 or Ru(NCHPh)Cl2(PCy3)2.
yields. Herein we report the extension of this work to the
synthesis of more highly functionalised b-lactams.
Sequential reaction of the commercially available 4-acet-
oxyazetidin-2-one 3 with allyl alcohol and ethyl glyoxylate
produced the diastereomeric alkenes 4a,b (Scheme 1) which
were separable by chromatography. Protection of 4a and 4b
with tert-butyldimethylchlorosilane gave the metathesis sub-
strates 5a,b† in quantitative yield. In a similar manner treatment
of 4-acetoxyazetidin-2-one 3 with allyl alcohol followed by
benzyl bromide or tert-butyldimethylchlorosilane gave alkenes
7a (69%) and 7b (76%) respectively. Reaction of 5a with excess
styrene (4 equiv.) and a catalytic amount of carbene 1 (1 mol%)
in dichloromethane at room temperature for 2 h produced the
desired alkene 6a (79%) (Scheme 1). Similarly epimer 5b gave
6b under the same conditions in comparable yield (67%). In all
the cross metathesis processes reported herein only the trans
double bond isomers were observed. We then explored a series
of electronically diverse styrenes (p-Cl, p-OMe, p-Me) as the
cross metathetic partners of protected b-lactams 7a and 7b. The
reactions proceeded smoothly in the presence of 1 (1 mol%) to
furnish trans alkenes 8a–f (42–66%) (Scheme 2).
The elaboration of carbon skeletons via the construction of
carbon–carbon bonds represents one of the most important
endeavours in synthetic organic chemistry. Transition metal
catalysed processes are especially valuable, particularly for the
selective transformation of polyfunctional precursors into
products of enhanced complexity. The pioneering work of
Grubbs has shown that a wide variety of compounds may be
synthesised via ring-closing metathesis (RCM) procedures1
using molybdenum 12 and ruthenium 23 based catalysts. Other
workers have extended this methodology which is now finding
increasing use in synthesis.4–8 Our group has recently shown
that a number of previously unexplored systems are amenable to
alkene metathesis.9,10 In particular we have shown that b-
lactams are well tolerated under metathesis conditions furnish-
ing both mono- and bi-cyclic systems alike in good to excellent
The synthesis of novel heteroatom-containing b-lactam
substrates suitable for RCM were examined next. Following the
procedure of Uyeo11 a modified Sakurai-type reaction was
utilised to synthesise 4-allylazetidin-2-one 10 (Scheme 3).
Treatment of 4-acetoxyazetidin-2-one 3 with allylchloro-
dimethylsilane in the presence of an amine base followed by
PCy3
Cl
Ph
Ru
Pri
Pri
Ph
Cl
PCy3
N
(F3C)2MeCO
(F3C)2MeCO
Me
Me
Mo
1
2
OAc
O
O
R
C6H4-p-X
i, ii or
i, iii
iv
N
N
N
H
R
O
O
O
O
O
OAc
i, ii
3
7a R = Bn
b R = SiMe2But
8a R = Bn
b R = Bn
c R = Bn
X = Cl, 42%
X = OMe, 53%
X = Me, 51%
+
N
N
N
N
N
N
N
OH
OH
H
O
O
O
O
O
d R = SiMe2But X = Cl, 53%
e R = SiMe2But X = OMe, 52%
f R = SiMe2But X = Me, 66%
CO2Et
4b
CO2Et
4a
3
iii
iii
Scheme 2 Reagents and conditions: i, HOCH2CHNCH2, Zn(OAc)2, PhH,
heat, 4 h, 83%; ii, BrCH2Ph, NaH, DMF, 0 °C, 83%; iii, ButMe2SiCl, NEt3,
CH2Cl2, 0 °C, 92%; iv, 1 (1 mol%), p-X-C6H4CHNCH2, CH2Cl2, 25 °C
O
O
OSiMe2But
OSiMe2But
CO2Et
5a
O
CO2Et
5b
OAc
H
OAc
Si
ii
i
N
N
N
iv
iv
H
10
O
O
O
O
Me Me
O
Ph
OSiMe2But
O
Ph
OSiMe2But
3
9
iii
O
CO2Et
6b
CO2Et
6a
N
11
Scheme 1 Reagents and conditions: i, HOCH2CHNCH2, Zn(OAc)2, PhH,
heat, 4 h, 83%; ii, H(O)CCO2Et, PhMe, heat 15 h, 79%; iii, ButMe2SiCl,
DMAP, CH2Cl2, 25 °C, 2 d, 100%; iv, 1 (1 mol%), PhCHNCH2, CH2Cl2,
25 °C
Scheme 3 Reagents and conditions: i, ClSiMe2CH2CHNCH2, NEt3,
CH2Cl2, 25 °C, 15 h, 85%; ii, Me3SiOTf, CH2Cl2, 0 °C, 2 h, 71%; iii,
BrCH2CHNCH2, KOH, 18-crown-6, PhH, 25 °C, 2 h, 77%
Chem. Commun., 1997
155

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reaction with a catalytic quantity of trimethylsilyl trifluoro-
methanesulfonate (Me3SiOTf) gave 4-allylazetidin-2-one 10
(59% over 2 steps). This proved to be rather unstable and was
treated immediately with allyl bromide and potassium hydrox-
ide to give the diene 11 (77%). In an analogous manner
substrate 15 was synthesised, starting from commercially
available (3R,4R)-3-[(R)-tert-butyldimethylsilyloxyethyl]aze-
tidin-2-one 12 (Scheme 4, 46% over 3 steps). In this reaction
sequence the Me3SiOTf mediated allyl transfer to produce 14
from 13 was a stereoselective process furnishing a single
diastereomer. The novel diene 17 was obtained by sequential
treatment of 4-acetoxyazetidin-2-one 3 with prop-2-enethiol
and allyl bromide (Scheme 5, 56% over 2 steps). Alkene 19 was
synthesised by reaction of 4-acetoxyazetidin-2-one 3 with N-
tosylallylamine (67%) according to the procedure of Campbell
and Connarty12 followed by N-allylation of the resulting b-
lactam 18 with allyl bromide (89%).
With the RCM substrates in hand, diene 11 was exposed to a
catalytic quantity of ruthenium carbene 2 (5 mol%) in
dichloromethane at room temperature. Diene 11 was rapidly
converted into the bicyclic [2.4.0]carbacephem 20 in excellent
yield (81%) (Scheme 7). In this and the other RCM processes
(vide infra), only a single product component was evident by
TLC analysis. In a similar manner diene 15 was converted into
carbacephem 23 in high yield (Scheme 8, 78%). RCM of dienes
17 and 19 proceeded only slowly with ruthenium catalyst 2 (5
mol%) giving bicyclic lactams 21 and 22 in low isolated yield
(22 and 36% respectively). However, replacement of the
ruthenium catalyst 2 with the molybdenum catalyst 1 (5 mol%)
resulted in rapid reactions leading to the isolation of homo-
cephem 21 (78%) and homo-azacephem 22 in excellent yield
(91%) (Scheme 7).
OSiMe2But
OSiMe2But
OAc
OSiMe2But
OAc
Me
Me
Me
ii
i
N
N
N
Si
H
H
O
O
O
14
Me Me
12
13
iii
OSiMe2But
Me
In conclusion we have shown that alkene metathesis is an
extremely useful synthetic tool for the synthesis of highly
functionalised monocyclic b-lactams and a variety of bicyclic
b-lactams. The range of heteroatoms tolerated in the ring-
closing metathesis reaction (C, O, N and S) suggests that this
methodology should be of enormous use for the synthesis of a
great range of antibiotics and their derivatives. The azacephem
system is of particular interest as this is a relatively unexplored
area. Recent work on azapenems has been published by
Hegedus13,14 and our work provides an alternative metal-
mediated route to such systems.
N
O
15
Scheme 4 Reagents and conditions: i, ClSiMe2CH2CHNCH2, NEt3,
CH2Cl2, 25 °C, 15 h, quant.; ii, Me3SiOTf, CH2Cl2, 0 °C, 2 h, 91%; iii,
BrCH2CHNCH2, KOH, 18-crown-6, PhH, 25 °C, 2 h, 92%
OAc
H
S
S
i
ii
N
N
N
O
O
O
3
16
17
We thank Glaxo Wellcome Research Ltd. for the most
generous endowment (to A. G. M. B.) and for a CASE grant (to
S. P. D. B.), the Wolfson Foundation for establishing the
Wolfson Centre for Organic Chemistry in Medical Science at
Imperial College, and the Engineering and Physical Science
Research Council for a CASE grant (to S. P. D. B.).
Scheme 5 Reagents and conditions: i, HSCH2CHNCH2, NaOMe, MeOH,
25 °C, 90 min, 69%; ii, BrCH2CHNCH2, NaH, DMF, 0 °C, 1 h, 81%
Me
ii
Me
OAc
H
O2S
N
O2S
N
i
Footnote
N
† All new compounds were fully characterised spectroscopically and further
by microanalysis and/or HRMS.
O
N
N
H
O
O
3
18
19
References
Scheme 6 Reagents and conditions: i, p-MeC6H4SO2NHCH2CHNCH2,
KOBut, 18-crown-6, MeCN, 25 °C, 30 min, 67%; ii, BrCH2CHNCH2, NaH,
DMF, 0 °C, 1 h, 89%
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X
(
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n
(
)
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i
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N
N
O
O
11 X = CH2, n = 0
17 X = S, n = 1
19 X = p-MeC6H4SO2N, n = 1
20 X = CH2, n = 0
21 X = S, n = 1
22 X = p-MeC6H4SO2N, n = 1
Scheme 7 Reagents and conditions: i, X = CH2, n = 0, 2 (5 mol%),
CH2Cl2, 25 °C, 6 h, 81%; i, X = S, n = 1, 1 (5 mol%), CH2Cl2, 25 °C,
2 h, 78%: i, X = p-MeC6H4SO2N, n = 1, 1 (5 mol%), CH2Cl2, 25 °C, 2 h,
91%
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OSiMe2But
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i
Me
Me
N
N
O
O
15
23
Scheme 8 Reagents and conditions: i, 2 (5 mol%), CH2Cl2, 25 °C, 6 h,
78%
Received, 28th October 1996; Com. 6/07308E
156
Chem. Commun., 1997