- Email: [email protected]
Synthesis and Properties of β-sultams
Tetrahedron Letters,Vol.24,No.21,pp Printed in Great Britain
2131-2134,1983
0040-4039/83/212131-04$03.00/o 01983 Pergamon Press Ltd.
SYNTHESIS AND PROPERTIES OF E-SULTAMS Wolfgang
Roller*,
Adolf
Linkies,
HOECHST ARTIENGESELLSCHAFT,
Herbert
Reeling,
D 6230 Frankfurt
Dieter
Heuschling
(Main) 80
Abstract: B-Sultams substituted in 2- and 3-position including bicyclic B-sultams were prepared and some of their reactions are reported. In contrast to B-lactams little attention has previously been paid to E-sultams. 1) Scanning the literature 2) chlorination of amino-mercaptans in the presence of alcohol to sulfochlorides by cyclisation to B-sultams
(2) and -disulfides
(3) (CClr/EtOH/C12/+10°) followed
(4) (EtaN, CH&l I, 0') proved to be the most versatile
method for the preparation of this biologically interesting class of compounds. The amino-mercaptans and the disulfides
(6)
(2) were obtained from aziridines
(6) from aminothiosulfates
(l-1with HIS (path Aj3),
(2) with iodine (path B).4)
path A
RLNc~
w
I
path B
l [
The 8-sultams thus prepared are listed in table 1. 4b,S) Since the corresponding thiosulfate was obtained from natural S-prolin the bicyclic I+slltam (&I) is optically active and has the same absolute configuration at the bridgehead as the E-lactam antibiotics. 7)
2131
2132
Lable 1 R2
2 4c 4d 4e 4f 4g 4h 41
H CH, H CH> H CHzCH2OH H CHZCHZCOZCZ~S H CHZCH~CGHS H CHzCHrCHp H CHzCHrCN -CHrCHrCHr-CHzCHzCHrCHr-
R3
yield
H CHB H H H H H H H
69 74 26 96 95 44 75 78 63
path
% % % % % % % % %
The chemical properties of E-sultams are in many respects comparable with those of 5-lactams. For example, it was possible to alkylate the E-sultam (1) according to a phase-transfer method which had been developed for B-lactams. 8) Activated alkyl halides such as allylbromide and benzylbromide reacted quickly. With a-bromoacetic esters, which are partially hydrolyzed under these conditions the yield tended to be lower, and secondary alkyl halides such as isopropyl iodide were hardly converted. The E-sultams
(2) which were obtained by phase-transfer
alkylation are listed in table 2. I-l V-K,
R-X
-
+
rl O,S-kR s
1 table 2 R 8a 8b t; :z t,9
CH, n-C&i13 -CHrCH=CHr -CHrCsHI I-CJH, -CHrCOrCHpCsH~ -CHrCOzCrH5 -CHrC02CH~
X
yield
J Br Br Br J Br Br Br
50 % 76 % 72 % 76 % 3% 47 % 31 % 22 %
Since acylation of the B-SuItam (7) in l-position causes destabilisation of
the
4-membered ring the yield of isolated products tended to be low. A good yield of (lOa) was obtained by the reaction of (7) with methylchloroformate(C1~rCH~/~N/ and (10~) were prepared by acylation of the CH2C11/00). Small amounts of (lob) sodium salt (1) with acetyl chloride and benzoyl chloride respectively. The compounds
(lOa-c) decomposed at room temperature but it was possible to store --
them in a freezer for several weeks.
2133
m acid
&dtam
(1)
reacted
parafonnaldehyae @kOH/Et~N/C&O)n)
with
to
(I&)
and
witi glyoxylic
(HzO/KHCO~/(OH)~CHCO~H) to (lzb). Cciwersicol Of (1) with IEthyliSaZpnate c&c12/CHsccV -
E&N) gave the urea derivative(13).Silylationof (7) to (2) redily occunedtithcbl.0~ trimethyl-sUane ((=H2C12/CH3SiC1/Et~N/5-200).
l-l 0$--N
OH T
-10a R=OCH3 10b R-CH3 -
27 %
100 % 57 %
2 %
-1Oc R=Ph
l-l
12a R=H 12b R=C02X -
82 %
7
a7
l-l
%
ozS-NTNNcH3
O,S-N,
13 -
14 -
70 Si(CH,),
R3
r-FR2
.
02s-N,R1 Ia
A3
;k;=R'=H
1
j&
E -NHR’
HO,SCH,-
3, R'=R'=H
R'=H, R'=R'=CH3
15a -
R’=R2=R3=H
15b 15~ -
R'=CH3, R'=R"=H R'-H, R'=R3=CH3
YH3 .
HO,C-CHrC-NH,
17 -
-16
Ph c
4i -
18 -
%
2134
Inordertofindout~reaboutthestabilityofB-sultams~imrestigatedtheringopeningof (Z), K&, and (4b) to @),
with the 8-E
(l5J
(16) .g) At@13
hw slcklerbya factor of 8
and @I
in aqueous solutions and CaqJaEd the B-sultam @,
the half life of (&) was 45min. The ring openzing of (7)
and the
ring openingof (4&) slm
B-lactzm (16)kas cwwztedonlyhalfasfastas between E-&tams and B-lactamswaseven-
(*) at#13.Tbedifference
(16)w
in stability
drasticin acidic soluti~. !tk half
(4&)atpH 2.3 is12 minuheras (16)rem&xedmed m31-ethan 24 h. e
by a factorof 3CO;')Ihe
life of
in an aqueoussolutkm at this pH for
readilyconvertedto (z) at 90' with an equivalentamxnt
of xl. Like the B-lactam (16)the investigatedB-sultamswere stabletoward amines inaprotic solventsatroanteqeram. benzylamineat teqeram
Thebicyclic B-s&tam (3) axldcailybe wnvertedto @)
with
above 140'. The synthesisof abicyclic B-sultamvkse strwtwe
isrelatedtothatofpenic~inwillbereportedshortly.~)
1)
Accordingto the JUPAC nanenclaturethe systematicname for 5-sultamis 1,2-thiazetidin-l,l-
93, 784 (1960). 2.3) H.Bqaw, G.Dransch,C&m.&. E.Bellasio,E.Testa,Helx'.Cl&.ELI=ta45_, 717 (1962). W B.J.R.Nicolaus,
w
G.M.AUcins,E.M.Buq~s, J.Am.Chen.Soc. g,
2502 (1967)and 90, 4744 (1968).
43, 3543 (1970). 24 O.Tsugeand S.Iwanan& Bull.C!hem.Soc.Jpn. 2e) A.Le Berre, J-Petit,TetrahedronLett. 3, 213 (1972). 2f) T.Nagai,T,Shiqaki, M.Inagaki,T.Oh&ima, Bull.Chem.Scc.J~.2, llO2 (1979). patent 710.267 (1941). 34 H.Bestian,m H.Bestian, Ann.-. 566, 210 (1950). W W
E.J.MUls, M.T.Bcg&, J.Am.Ckem.Soc. 62, ll73 (1943).
4a) D.%senthal, G.Bxandrq, K.H.Davis,Jr., M.E.Wall,J.Org.Chem.2, 3689 (1965). 28, 981 (1963). 4b) J.R.Piper,T.P.Jdmstm, J.0q.Chm.1. (IR,'Hand'3CNMR,andMS) 5) mmgavespectraldata struchlres.~e~a~~infw~ringsulfaryl~6)~ alsorevealedin5-sulmby
13C m.
in acun&xewiti
their
~(C!DZl~)(1) 61.2; (4a) 66.4; (4&) 70.8 and -
(4h) 64.7 ppn. D.C.Ditmer,B.H.Paw, 6) E&&c, A.A.Bazzi,J.B.Iambert,S.M.%arq, X.K.Andersen, D.J.H.Smiti,J.Org.Chen.45, 4807 (1980). 7)
(s): m.p. 51-52O, [alD=2.2“(inmethanol01).
H.Pietsch,A.Unkies, Tetrahedropl L&t. 615 (1978). 8) D.Reuschling, 9) Ihe~~eremniteredbyNMRat30~. 10) F.Cavagnar W.IQller, A.Linkies, H.&hling, D.Reuschling, Angew.C!hem.Sq~1.,1962,1201-1212 (Received
in Germany
27 Flay 1982)
2131-2134,1983
0040-4039/83/212131-04$03.00/o 01983 Pergamon Press Ltd.
SYNTHESIS AND PROPERTIES OF E-SULTAMS Wolfgang
Roller*,
Adolf
Linkies,
HOECHST ARTIENGESELLSCHAFT,
Herbert
Reeling,
D 6230 Frankfurt
Dieter
Heuschling
(Main) 80
Abstract: B-Sultams substituted in 2- and 3-position including bicyclic B-sultams were prepared and some of their reactions are reported. In contrast to B-lactams little attention has previously been paid to E-sultams. 1) Scanning the literature 2) chlorination of amino-mercaptans in the presence of alcohol to sulfochlorides by cyclisation to B-sultams
(2) and -disulfides
(3) (CClr/EtOH/C12/+10°) followed
(4) (EtaN, CH&l I, 0') proved to be the most versatile
method for the preparation of this biologically interesting class of compounds. The amino-mercaptans and the disulfides
(6)
(2) were obtained from aziridines
(6) from aminothiosulfates
(l-1with HIS (path Aj3),
(2) with iodine (path B).4)
path A
RLNc~
w
I
path B
l [
The 8-sultams thus prepared are listed in table 1. 4b,S) Since the corresponding thiosulfate was obtained from natural S-prolin the bicyclic I+slltam (&I) is optically active and has the same absolute configuration at the bridgehead as the E-lactam antibiotics. 7)
2131
2132
Lable 1 R2
2 4c 4d 4e 4f 4g 4h 41
H CH, H CH> H CHzCH2OH H CHZCHZCOZCZ~S H CHZCH~CGHS H CHzCHrCHp H CHzCHrCN -CHrCHrCHr-CHzCHzCHrCHr-
R3
yield
H CHB H H H H H H H
69 74 26 96 95 44 75 78 63
path
% % % % % % % % %
The chemical properties of E-sultams are in many respects comparable with those of 5-lactams. For example, it was possible to alkylate the E-sultam (1) according to a phase-transfer method which had been developed for B-lactams. 8) Activated alkyl halides such as allylbromide and benzylbromide reacted quickly. With a-bromoacetic esters, which are partially hydrolyzed under these conditions the yield tended to be lower, and secondary alkyl halides such as isopropyl iodide were hardly converted. The E-sultams
(2) which were obtained by phase-transfer
alkylation are listed in table 2. I-l V-K,
R-X
-
+
rl O,S-kR s
1 table 2 R 8a 8b t; :z t,9
CH, n-C&i13 -CHrCH=CHr -CHrCsHI I-CJH, -CHrCOrCHpCsH~ -CHrCOzCrH5 -CHrC02CH~
X
yield
J Br Br Br J Br Br Br
50 % 76 % 72 % 76 % 3% 47 % 31 % 22 %
Since acylation of the B-SuItam (7) in l-position causes destabilisation of
the
4-membered ring the yield of isolated products tended to be low. A good yield of (lOa) was obtained by the reaction of (7) with methylchloroformate(C1~rCH~/~N/ and (10~) were prepared by acylation of the CH2C11/00). Small amounts of (lob) sodium salt (1) with acetyl chloride and benzoyl chloride respectively. The compounds
(lOa-c) decomposed at room temperature but it was possible to store --
them in a freezer for several weeks.
2133
m acid
&dtam
(1)
reacted
parafonnaldehyae @kOH/Et~N/C&O)n)
with
to
(I&)
and
witi glyoxylic
(HzO/KHCO~/(OH)~CHCO~H) to (lzb). Cciwersicol Of (1) with IEthyliSaZpnate c&c12/CHsccV -
E&N) gave the urea derivative(13).Silylationof (7) to (2) redily occunedtithcbl.0~ trimethyl-sUane ((=H2C12/CH3SiC1/Et~N/5-200).
l-l 0$--N
OH T
-10a R=OCH3 10b R-CH3 -
27 %
100 % 57 %
2 %
-1Oc R=Ph
l-l
12a R=H 12b R=C02X -
82 %
7
a7
l-l
%
ozS-NTNNcH3
O,S-N,
13 -
14 -
70 Si(CH,),
R3
r-FR2
.
02s-N,R1 Ia
A3
;k;=R'=H
1
j&
E -NHR’
HO,SCH,-
3, R'=R'=H
R'=H, R'=R'=CH3
15a -
R’=R2=R3=H
15b 15~ -
R'=CH3, R'=R"=H R'-H, R'=R3=CH3
YH3 .
HO,C-CHrC-NH,
17 -
-16
Ph c
4i -
18 -
%
2134
Inordertofindout~reaboutthestabilityofB-sultams~imrestigatedtheringopeningof (Z), K&, and (4b) to @),
with the 8-E
(l5J
(16) .g) At@13
hw slcklerbya factor of 8
and @I
in aqueous solutions and CaqJaEd the B-sultam @,
the half life of (&) was 45min. The ring openzing of (7)
and the
ring openingof (4&) slm
B-lactzm (16)kas cwwztedonlyhalfasfastas between E-&tams and B-lactamswaseven-
(*) at#13.Tbedifference
(16)w
in stability
drasticin acidic soluti~. !tk half
(4&)atpH 2.3 is12 minuheras (16)rem&xedmed m31-ethan 24 h. e
by a factorof 3CO;')Ihe
life of
in an aqueoussolutkm at this pH for
readilyconvertedto (z) at 90' with an equivalentamxnt
of xl. Like the B-lactam (16)the investigatedB-sultamswere stabletoward amines inaprotic solventsatroanteqeram. benzylamineat teqeram
Thebicyclic B-s&tam (3) axldcailybe wnvertedto @)
with
above 140'. The synthesisof abicyclic B-sultamvkse strwtwe
isrelatedtothatofpenic~inwillbereportedshortly.~)
1)
Accordingto the JUPAC nanenclaturethe systematicname for 5-sultamis 1,2-thiazetidin-l,l-
93, 784 (1960). 2.3) H.Bqaw, G.Dransch,C&m.&. E.Bellasio,E.Testa,Helx'.Cl&.ELI=ta45_, 717 (1962). W B.J.R.Nicolaus,
w
G.M.AUcins,E.M.Buq~s, J.Am.Chen.Soc. g,
2502 (1967)and 90, 4744 (1968).
43, 3543 (1970). 24 O.Tsugeand S.Iwanan& Bull.C!hem.Soc.Jpn. 2e) A.Le Berre, J-Petit,TetrahedronLett. 3, 213 (1972). 2f) T.Nagai,T,Shiqaki, M.Inagaki,T.Oh&ima, Bull.Chem.Scc.J~.2, llO2 (1979). patent 710.267 (1941). 34 H.Bestian,m H.Bestian, Ann.-. 566, 210 (1950). W W
E.J.MUls, M.T.Bcg&, J.Am.Ckem.Soc. 62, ll73 (1943).
4a) D.%senthal, G.Bxandrq, K.H.Davis,Jr., M.E.Wall,J.Org.Chem.2, 3689 (1965). 28, 981 (1963). 4b) J.R.Piper,T.P.Jdmstm, J.0q.Chm.1. (IR,'Hand'3CNMR,andMS) 5) mmgavespectraldata struchlres.~e~a~~infw~ringsulfaryl~6)~ alsorevealedin5-sulmby
13C m.
in acun&xewiti
their
~(C!DZl~)(1) 61.2; (4a) 66.4; (4&) 70.8 and -
(4h) 64.7 ppn. D.C.Ditmer,B.H.Paw, 6) E&&c, A.A.Bazzi,J.B.Iambert,S.M.%arq, X.K.Andersen, D.J.H.Smiti,J.Org.Chen.45, 4807 (1980). 7)
(s): m.p. 51-52O, [alD=2.2“(inmethanol01).
H.Pietsch,A.Unkies, Tetrahedropl L&t. 615 (1978). 8) D.Reuschling, 9) Ihe~~eremniteredbyNMRat30~. 10) F.Cavagnar W.IQller, A.Linkies, H.&hling, D.Reuschling, Angew.C!hem.Sq~1.,1962,1201-1212 (Received
in Germany
27 Flay 1982)