A regio and stereospecific synthesis of carbacephem antibiotics

Article abstract of DOI:10.1055/s-1999-3167

In this article we report a short and practical route to chiral carbacephems 1 based on an asymmetric Staudinger reaction for building the β-lactam ring, and on a tandem elimination-conjugate addition for making the second ring.

Full text of DOI:10.1055/s-1999-3167

LETTER
1441
A Regio and Stereospecific Synthesis of Carbacephem Antibiotics
Gema Ruano, Josefa Anaya*, Manuel Grande
Departamento de Química Orgánica, Universidad de Salamanca, E-37008 Salamanca, Spain.
Fax +34 23 294574; E-mail: janay@gugu.usal.es; mgrande@gugu.usal.es
Received 15 June 1999
Dedicated to the late Dr. Stephan D. Gero with deep affection
tam nucleus that can be attached either to C-4 (10), to N-
1 (11) or to both positions (8), as shown in Scheme 2.
Deprotection of dithioacetal groups in 4 and 5 with
PhI(OCOCF3)211 in the presence of NaHCO3 afforded the
respective aldehydes 6 (85%) and 7 (95%) which were re-
acted with Ph3P=CHCO2Me to give 8 (54%) and 9 (63%)
respectively. Reduction of aldehyde 6 with NaBH4 in
EtOH followed by methanesulfonation afforded 10 in
56% yield. Selective ozonolysis6 of 9 using NaBH4 as re-
ducing agent gave an alcohol whose methanesulfonation
provided 11 in 50% yield.
Abstract: In this article we report a short and practical route to
chiral carbacephems 1 based on an asymmetric Staudinger reaction
for building the b-lactam ring, and on a tandem elimination-conju-
gate addition for making the second ring.
Key words: D-glucosamine, asymmetric Staudinger reaction, b-lac-
tam, tandem ring-closure, carbacephem.
Carbacephems 1 are known to exhibit antibiotic activity
and have increased chemical stability compared to cepha-
losporins.1 They are usually synthesized2,3 by making the
b-lactam ring and then the six-membered ring, either by
formation of the N-1/C-25 or the C-2/C-3 s-bonds,4 al-
though a recent C-3/C-4 cyclization via alkene metathesis
has been reported.5
R1
MeO
SR0
N
O
SR0
H
5'
3'
O
4: R0 = - Pr, R1 = -CO2Bn
5: R0 = - (CH2)3 -, R1 = -Ph
4'
O
7'
6'
7'
O
O
O
O
O
R
R
R
7
6
3
4
4
= SG
5
2
i
1
8
2
N
N
N
R'
1
3
O
O
O
R'
5
R1
H
R1
8'
MeO
MeO
6
H
3
4
SG
O
CO2H
ii
2
1
3
O
1'
O
N
CHO
SG
N
CO2Me
vii
2'
O
O
O
H
H
SG
= SG
8: R1 = -CO2Bn
9: R1 = -Ph
iii
6: R1 = -CO2Bn
7: R1 = -Ph
iv
Scheme 1
MeO
MeO
In a previous paper6 we described the attempts to synthe-
size carbacephams 2 (precursors of carbacephems 1)7
from some chiral 4-acetyl-N-substituted monobactams 3
by intramolecular displacement under ionic conditions at
low temperature (Scheme 1). This strategy did not give
the desired carbocycle 2 perhaps because of the steric re-
quirements of the sugar residue SG.
CO2Bn
OMs
N
v
v
2
vi
vii
N
CO2Me
O
OMs
O
H
SG
H SG
10
11
vii
vi
MeO
MeO
R4
CO2Bn
OMs
This sugar group introduced as a chiral auxiliary, is found
as a substituent in several monocyclic b-lactams which act
as selective inhibitors of human leukocyte elastase
(HLE),8 and this is the reason why we are interested in
maintaining it in the carbocyclic b-lactam derivatives.
Hence, we examined the viability of tandem conjugate ad-
ditions in order to synthesize carbacepham and carba-
cephem systems with the sugar residue SG at C-2.
N
N
CO2Me
O
O
H
SG
SG
13: R4 = - CH2OMs
14: R4 = - CH=CH-CO2Bn
12
Reagents and conditions: i, PhI(OCOCF3)2 (1.5 mmol), NaHCO3 (3.0
mmol), CH3CN:H2O (9:1), r.t.; ii, Ph3P=CH-CO2Me (1.2 mmol),
THF, r.t..; iii, NaBH4 , 0°C, then MsCl, pyridine/DMAP; iv, O3, Su-
dan Red 19 (0.05 mmol%), CH2Cl2-MeOH (8:2), -78°C, NaBH4,
0°C, then MsCl, pyridine/DMAP; v, Me2CuLi, THF, -20°C; vi, Red-
Al, CuBr, THF, -78°C; vii, BnNH2, MeOH, r.t.
Three different approaches for elaborating the precursor
carbacephams 2 from the readily accessible 1,3,4-trisub-
stituted azetidin-2-ones 49 and 510 were envisaged. They
differ in the location of the Michael acceptor in the b-lac-
Scheme 2
Synlett 1999, No. 9, 1441–1443 ISSN 0936-5214 © Thieme Stuttgart · New York

1442
G. Ruano et al.
LETTER
CO2Bn
CO2Me
CO2Bn
CO2Me
CO2Bn
6'
MeO
i
MeO
MeO
7
6
5
ii
4
N
8
CO2Me
O
N
N
iii
3
+
+
1
8
O
O
2
O
iv
v
O
1'
O
5'
4'
2'
3'
O
O
O
O
5'
O
O
O
15
16
17
Reagents: i, LDA ; ii, LHMDS; iii, NaHMDS; iv, LSA; v, phosphazene base P1-t-Bu. Conditions: THF, -78°C.
Scheme 3
R2NLi
a
OMe
H
O
CO2Bn
O
CO2Bn
CO2Et
MeO
CO2Bn
CO2Me
MeO
c
N
SG
15
N
2'
N
O
O
H
OMe
H
H
SG
b
c
O
B
4'
R2NLi
LiNR2
O
8
O
J= 10.2 Hz
O
J= 5.0 Hz
CO2Bn
A
J= 13.4 Hz
H5
H4
H7 H6
MeO
(CH3)2CO
CO2Me
CO2Bn
CO2Me
N
O
15
MeO
O
SG
17
16
N
H
O
C
R
Possible mechanisme for the formation of compounds 15, 16 and 17.
Scheme 4
The monobactams 10 and 11 were first tested to study the tained when LSA16 was used; in this case the carbacephem
role of different reagents and reaction conditions as well 15 was isolated in a non optimized 30% yield together
as the location of the nucleophile and Michael acceptor in with the compounds 16 (20%) and 17 (15%).
the intramolecular cyclisations. Unfortunately, we did not
The structure of these compounds 15, 16 and 17 were rig-
succeed in the conversion of the above monobactams into
orously established by 2D COSY, HMQC, HMBC and 1D
the respective 4,5-disubstituted and 3,4-disubstituted car-
NOE experiments. The observed coupling constants
bacephams. Treatment of these monobactams 10 and 11
(Scheme 4) and the NOE between H-6/H-4 and H-6/H-7
in 15 established the relative trans configuration for H-4,
H-5 and H-6. As the absolute configuration for C-6 and C-
7 was known, the configuration of the carbacephem skel-
either with Me2CuLi in ether12 at -20 oC or with Red-Al® /
CuBr in THF13 at -78 oC gave the starting material togeth-
er with b-lactam ring open products or the saturated
monobactam 12. Lastly, benzyl amine,14 a softer base, was
eton was assigned (4R, 5R, 6R, 7S) for 15.17
tested on 11 but apart from the starting material the sole
Although the LSA could react with 8 by conjugate
reaction product isolated was identified as compoud 13
addition14 (Scheme 4, routes a and b), the formation of the
observed reaction products can be explained by abstrac-
tion of the allyl hydrogen atom H-2’by the LSA under ki-
netic conditions (route c) with formation of the dienolate
(44%). Similar results were obtained in the treatment of 8
with BnNH2 under thermodynamic conditions to give 14
(80%).
In marked contrast with the above results, the diester 8 un-
anion A which can adopt the geometry shown in B to give
derwent a 6-[enol-exo]-exo-trig cyclisation when treated
the carbacephem 15. The diastereoselectivity of this last
intramolecular cyclisation is in agreement with a chair-
with LDA, LiHMDS, NaHMDS, lithium N-benzyl-N-tri-
methylsilylamide (LSA) and Phosphazene Base P1-t-Bu15
like conformation of the transition state in which the C-4
in THF at -78oC (Scheme 3). The best results were ob-
and C-5 substituents are equatorial.
Synlett 1999, No. 9, 1441–1443 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Regio and Stereospecific Synthesis of Carbacephem Antibiotics
1443
(15) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1992.
On the other hand, the enolate A can progress through an
alkoxide at C-4’, C, to compounds 16 and 17 by intramo-
lecular cyclisation.
(16) Uyehara, T.; Shida, N.; Yamamoto, Y. J. Chem. Soc., Chem.
Commun., 1989, 113. Uyehara, N.; Asao, N.; Yamamoto, Y.
J. Chem. Soc., Chem. Commun., 1989, 753. Uyehara, T.;
Shida, N.; Yamamoto, Y. J. Org. Chem., 1992, 57, 3139.
(17) Selected physical data of key compounds 8 and 15. 4b-(E-2-
Benzyloxycarbonyl-1-ethene)-1[(1’,2’-dideoxy-3’,4’;5’,6’-di-
O-isopropylidene-1’,1’-(E-2-ethoxycarbonyl-1-ethenyl)-D-2’-
glucosyl]-3b-methoxy-azetidin-2-one (8): Rf= 0.25 (SiO2,
hexane/AcOEt 7:3). [a]D2 3 = +60.4 ( c= 1, CHCl3). IR n =
1767, 1728, 1661, 1516, 1383, 1260, 1067, 845. 1H NMR (200
MHz, CDCl3) d = 1.28, 1.31, 1.37 (3s, 12H, C(CH3)2); 3.40 (s,
3H, OCH3); 3.61 (s, 3H, CO2CH3); 3.62 (dd, J2’,1’= 7.8 Hz,
The optimization of the above reported strategy for the
preparation of carbacephem 15 as well as the study on the
transformation of compound 16 into carbacephems 15 are
in progress.
Acknowledgement
We thank the Junta de Castilla y León for its financial support
(Proyecto SA22/97) as well as the Spanish Ministerio de Educación
y Ciencia for a grant to one of us (G. R.).
J
2’,3’= 2.2 Hz, 1H, H2’); 3.69 (t, J4’,3’= J4’,5’= 7.4 Hz, 1H, H4’);
3.88 (dd, J6’a,6’b = 7.8 Hz, J6’a,5’= 4.8 Hz, 1H, H6’a); 3.92 (dd,
6’b,6’a = 8.0 Hz, J6’b,5’= 5.6 Hz, 1H, H6’b); 3.97-4.23 (m, 2H,
J
References and Notes
H3’, H5’); 4.55 (dd, J4,3 = 4.7 Hz, J4,5 = 9.1 Hz, 1H, H4); 4.64
(d, J3,4 = 4.7 Hz, 1H, H3); 5.15 (d, J = 12.4 Hz, 2H,
(1) Mochida, K.; Ogasa, T.; Shimada, J.; Hirata, T.; Sato, K.;
Okachi, R. J. Antibiot., 1989, 42, 283.
(2) For a review see: Kant, J.; Walker, D. G. In The Organic
Chemistry of b-Lactams; Georg, G. I., Ed.; VCH: New York,
1993; p 121.
(3) For recent contributions see: Guzzo, P. R.; Miller, M. J. Org.
Chem., 1994, 59, 4862. Metais, E.; Overman, L. E.;
Rodríguez, M. I.; Stearns, B. A. J. Org. Chem., 1997, 62,
9210.
(4) The numbering of the cephem system is given according to the
I.U.P.A.C. rules (Pure Appl. Chem., 1995, 67, 1307).
(5) Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles, M.
R.; Marshall, E. L.; Procopiou, P. A. J. Chem. Soc., Chem.
Commun., 1997, 155.
CO2CH2Ph); 6.03 (dd, J8’,1’= 15.6 Hz, J8’,2’= 0.7 Hz, 1H, H8’);
6.12 (d, J6,5 = 15.7 Hz, 1H, H6); 6.79 (dd, J1’,8’= 15.6 Hz, J1’,2’
= 7.8 Hz, 1H, H1’); 6.90 (dd, J5,6 = 15.7 Hz, J5,4 = 9.2 Hz, 1H,
H5); 7.30-7.39 (m, 5H, HPh).13C NMR (50.33 MHz, CDCl3) d
= 25.1, 26.3, 27.1, 27.4 (4C, C(CH3)2); 51.5 (CO2CH3); 54.5
(C4); 58.8 (OCH3); 60.8 (C2’); 66.4 (CO2CH2Ph); 67.7 (C6’);
77.0, 79.2, 80.1 (C3’, C4’, C5’); 85.5 (C3); 110.2, 110.5 (2C,
C7’); 125.1 (C8’); 126.4 (C6); 128.1, 128.2, 128.5 (5C, CHPh);
135.8 (CPh); 141.3, 142.9 (C1’, C5); 164.8, 165.6 (CO2CH2Ph,
CO2CH3); 166.5 (C2). 5a-Benzyloxycarbonylmethyl-
2b[(1’,2’;3’,4’-di-O-isopropylidene)-1,2,3,4-D-arabino-
tetrahydroxybutyl]-7b-methoxy-4b-methoxycarbonyl-6b-
carbacephem (15): Rf = 0.27 (SiO2, hexane/AcOEt 7:3).
[a]D2 3= +116 (c = 0.9, CDCl3). IR n = 1765, 1738, 1732,
1452, 1381, 1215, 1167, 1069, 843. 1H NMR (400 MHz,
CDCl3) d = 1.33, 1.36, 1.42, 1.45 (4s, 12H, C(CH3)2); 2.39-
2.45 (m, 2H, H6’a, H5); 2.69 (d, J6’b,6’a = 13.4 Hz, 1H, H6’b);
3.57 (s, 3H, OCH3); 3.58 (s, 3H, CO2CH3); 3.58 (dd, J4,3 = 6.0
Hz, J4,5 = 13.4 Hz, 1H, H4); 3.97 (dd, J6,7 = 5.0 Hz, J6,5 = 10.2
Hz, 1H, H6); 4.00 (dd, J4’a,4’b = 8.4 Hz, J4’a,3’= 5.2 Hz, 1H,
H4’a); 4.09 (dd, J4’b,4’a = 8.4 Hz, J4’b,3’= 6.1 Hz, 1H, H4’b); 4.11-
4.15 (m, 1H, H2’) 4.18-4.23 (m, 1H, H3’); 4.61 (d, J7,6 = 5.0 Hz,
1H, H7); 4.73 (d, J1’,2’= 8.1 Hz, 1H, H1’); 5.11 (d, J = 12.7 Hz,
1H, CO2CHHPh); 5.13 (d, J = 12.7 Hz, 1H, CO2CHHPh);
(6) Hernando, J. I. M.; Laso, N. M.; Anaya, J.; Gero, S. D.;
Grande, M. Synlett, 1997, 281.
(7) Anaya, J.; Barton, D. H. R.; Gero, S. D.; Grande, M.; Martín,
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(8) Adonias, M.; Anaya, J.; Cámara, J.; Canet, E.; Gateau-
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Bioorg. Med. Chem. Lett., 1993, 3, 2547. Anaya, J.; Gero, S.
D.; Grande, M.; Hernando, J. I. M.; Laso, N. M. Bioorg. Med.
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(9) Anaya, J.; Barton, D. H. R.; Caballero, M. C.; Gero, S. D.;
Grande, M.; Laso, N. M.; Hernando, J. I. M. Tetrahedron:
Asymm., 1994, 5, 2137.
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45, 1447.
5.36 (d, J3,4 = 6.0 Hz, 1H, H3); 7.25-7.42 (m, 5H, HPh); 13
NMR (100 MHz, CDCl3) d = 25.3, 26.5, 26.7, 26.9 (4C,
C(CH3)2); 30.7 (C5); 33.0 (C6’); 40.6 (C4); 51.9 (CO2CH3);
52.2 (C6); 58.9 (OCH3); 66.0 (C4’); 66.4 (CO2CH2Ph); 76.0
(C3’); 77.0 (C1’); 80.7 (C2’); 83.9 (C7); 105.7 (C3); 109.4, 109.9
(2C, C5’); 128.2, 128.3, 128.4, 128.5 (5C, CHPh); 135.2 (C2);
135.7 (CPh); 164.9 (CO2CH3); 171.1 (CO2CH2Ph); 171.7 (C8).
C
(13) Semmelhack, M. F.; Stauffer, R. D.; Yamashita, A. J. Org.
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Article Identifier:
1437-2096,E;1999,0,09,1441,1443,ftx,en;L08899ST.pdf
Synlett 1999, No. 9, 1441–1443 ISSN 0936-5214 © Thieme Stuttgart · New York