A new convenient synthesis of 3-carboxycephems starting from 7-aminocephalosporanic acid (7-ACA)

Article abstract of DOI:10.1002/1099-0690(200107)2001:13<2529::AID-EJOC2529>3.0.CO;2-9

New convenient syntheses of 3-carboxycephems starting from 7-ACA are reported. All three possible cephem derivatives with respect to the position of the double bond in the six-membered ring and oxidation state of the sulfur atom have been synthesized in high overall yield.

Full text of DOI:10.1002/1099-0690(200107)2001:13<2529::AID-EJOC2529>3.0.CO;2-9

FULL PAPER
A New Convenient Synthesis of 3-Carboxycephems Starting from
7-Aminocephalosporanic Acid (7-ACA)
Rolf Keltjens,[a] Subramanian K. Vadivel,[a] Erik de Vroom,[b] Antonius J. H. Klunder,[a] and
Binne Zwanenburg*[a]
Keywords: Antibiotics / Oxidations / Lactams / Carboxylic acids
New convenient syntheses of 3-carboxycephems starting
six-membered ring and oxidation state of the sulfur atom
from 7-ACA are reported. All three possible cephem derivat- have been synthesized in high overall yield.
ives with respect to the position of the double bond in the
Introduction
In this paper, we describe a general synthesis for 3-car-
boxycephems starting from the readily available 7-amino-
cephalosporanic acid (7-ACA) 1 as the starting material
and 3-formylcephems as the key intermediates (Scheme 1).
Although several syntheses of 3-carboxycephems have
been reported, no convenient general procedure for both
isomers with respect to the double bond in the six-mem-
bered ring has been described so far. Spry et al.[1Ϫ4] and
Peter et al.[5,6] were the first who synthesized the 3-carboxy-
cephem derivatives from the corresponding 3-formylceph-
2-ems in a sequence of reactions. In these approaches the
Results and Discussion
The general strategy for synthesizing our target com-
conversion of the formyl group into the carboxyl group in- pounds, viz. 3-carboxycephems 13, 14, 15, starting from 7-
volved at least four separate steps. Also starting from ce- ACA 1 involves protection of the C7-amino function and
phalosporin thiolactones, a multi step procedure (bromin- the C4-carboxyl function to allow a synthetic elaboration
ation, hydrolysis, oxidation and opening of the dioxo thi- at C10. The amino function was protected as a phenylaceta-
ophene ring) afforded the 3-carboxyceph-3-ems.[7Ϫ9] In ad- mide group because this moiety can be deprotected enzym-
dition, a few total syntheses have been reported.[10,11] Until atically and has successfully been used by others.[12Ϫ16] For
now, no method for the direct oxidation of the 3-formylce- the protection of the C4-carboxyl group we used the tert-
phems to the 3-carboxycephems has appeared in the literat- butyl ester because this environmentally benign and eco-
ure. Our interest in modifications at the C3-position of ce- nomically interesting group can be easily introduced. More-
phalosporins has led to an improved synthesis of 3-car- over, the re-conversion of the ester into the carboxylic acid,
boxycephems with the double bond in the ∆3 as well as in which may be rather problematic for these types of sub-
the ∆2 position.
strates, is high yielding in the case of the tert-butyl ester.[17]
Scheme 1
The amino group of 7-ACA 1 was protected with
phenylacetyl chloride under SchottenϪBaumann condi-
tions in 83% yield. Subsequently, the carboxyl group was
protected as a tert-butyl ester by treatment with dicyclo-
hexyl carbodiimide and tert-butyl alcohol using DMAP as
the catalyst. The only product obtained, after recrystallis-
ation, was the ∆2 isomer 4 in 88% yield (Scheme 2). This is
surprising since generally mixtures of the ∆2 and ∆3 isomers
[a]
Department of Organic Chemistry, NSR Institute for
Molecular Structure, Design and Synthesis, University of
Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax: (internat.) ϩ31 24 3653393
E-mail: Zwanenb@sci.kun.nl
[b]
DSM Anti-Infectives,
P.O. Box 1, 2600 MA Delft, The Netherlands
Eur. J. Org. Chem. 2001, 2529Ϫ2534
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0713Ϫ2529 $ 17.50ϩ.50/0
2529

R. Keltjens, S. K. Vadivel, E. de Vroom, A. J. H. Klunder, B. Zwanenburg
FULL PAPER
Scheme 2. a) Phenylacetyl chloride, H2O, pH 8.0, room temp., o/n, 83%. Ϫ b) m-CPBA, CH2Cl2, 0 °C, 1.5 h, 98%. Ϫ c) tBuOH, DCC,
DMAP (cat.), CH2Cl2, Ϫ30 °C Ǟ room temp., o/n, 88%. Ϫ d) i. cephalosporin acetyl hydrolase (CAH), H2O, pH 7.5, 4Ϫ8 h, ii. isoureum
(DCC, tBuOH), THF, o/n, 61%. Ϫ e) i. CAH, H2O pH 7.5, 4Ϫ8 h, ii. isoureum (DCC, tBuOH), THF, o/n, 62%. Ϫ f) NaOH, MeOH,
Ϫ20 °C, 4 h, 98%. Ϫ g) IBX, DMSO/THF, room temp., 30 h, 81%. Ϫ h) IBX, DMSO, room temp., 15Ј, 96%. Ϫ i) IBX, DMSO, room
temp., 15Ј, 95%. Ϫ j) NaClO2, cyclohexene, THF/phosphate buffer, 0° C, o/n, 93%. Ϫ k) NaClO2, cyclohexene, THF/phosphate buffer, 0
°C, 0%. Ϫ l) NaClO2, cyclohexene, THF/phosphate buffer, 0 °C, o/n, 80%. Ϫ m) AcCl, SnCl2, DMF, 0 °C, 2 h, 55%
are formed due to isomerization of the double bond.[18Ϫ20] scavenger, affording the 3-carboxyceph-2-em 13 in 93%
Under the basic reaction conditions the double bond had yield. This sequence for the conversion of 7-ACA into the
isomerized from the ∆3 to the ∆2 position driven by the 3-carboxyceph-2-em 13 only involves five steps, all of them
bulky acetoxy substituent at the C(10) position. Release of high yielding.
steric interference between the cis substituents of the ceph-
In principle, the synthesis of the corresponding 3-car-
3-em system can be invoked to explain this phenomenon. boxyceph-3-em 14 can be approached in a similar manner.
After saponification of the acetate at C10, alcohol 7 was After protection of the amino group, the acetate at C10 was
oxidised to aldehyde 10 with 1-hydroxy-1,2-benziodoxol- hydrolyzed with an immobilized enzyme (cephalosporin
3(1H)-one 1-oxide (IBX) analogous to the procedure of Fri- acetyl hydrolase) to obtain the hydroxy acid 5 in acceptable
gerio et al.[21] in 81% yield. Other well-known oxidation re- yield. Compound 5 must be handled with great care to pre-
agents (e.g. MnO2, PCC, Collins reagent, Moffat oxidation) vent lactonization under acidic conditions. To avoid the
gave lower yields, or did not react at all (e.g. TEMPO, formation of ∆2 by-products during the next protection
benzimidazolium dichromate under microwave conditions step, the esterification of the C4 carboxylic acid function
and isoquinolinium dichromate). The oxidation of the 3- was performed by treatment with the isourea derived from
formyl group to the carboxyl group was accomplished in a DCC and tert-butyl alcohol to give the tert-butyl ester 8 in
one step procedure by treatment with sodium chlorite in 62% yield.[22] As no base is required in this procedure, only
THF/phosphate buffer and cyclohexene as the chlorine ∆3 hydroxy ester 8 is formed. Oxidation of the alcohol func-
2530
Eur. J. Org. Chem. 2001, 2529Ϫ2534

A New Convenient Synthesis of 3-Carboxycephems
FULL PAPER
struments CHNSO EA 1108 element analyzer. Ϫ For the deter-
mination of optical rotations a PerkinϪElmer 241 polarimeter was
used. Ϫ Solvents were dried using the following methods: dichloro-
methane was distilled from P2O5; ethyl acetate was distilled from
K2CO3; diethyl ether was distilled from NaH; hexane and heptane
were distilled from CaH2; tetrahydrofuran was distilled from so-
dium prior to use. All other solvents were of analytical grade. Ϫ
Thin layer chromatography (TLC) was carried out on a Merck pre-
coated silica gel 60 F254 plates (0.25 mm). Spots were visualized
with UV or using a molybdate spray. Flash chromatography was
tion at C10 to the corresponding aldehyde 11 was achieved
again with IBX as the oxidizing agent in almost quantitat-
ive yield. Disappointingly, the formyl group could not be
oxidized directly to the corresponding carboxy group using
conditions similar to those used for the synthesis of 3-car-
boxyceph-2-em 13. Opening of the β-lactam ring probably
occurred by attack of a nucleophile (e.g. water) which has
also been observed by others.[23] The presence of an elec-
tron-withdrawing group on the C3-position (in conjugation
with the lactam moiety) also results in an enhanced chem- carried out at a pressure of ca. 1.5 bar, using Merck Kieselgel 60H.
ical reactivity of the β-lactam C6 carbonyl group.[2] Since
this route to the target compound 14 is not possible, a de-
Column chromatography at atmospheric pressure was performed
with ACROS silica gel (0.035Ϫ0.070 mm; pore diameter ca. 6 nm).
tour via sulfoxide 15 is worth considering. The results are
reported below.
Systematic names were generated using the ACD/Name program
provided by Advanced Chemistry Development Inc. (Toronto,
Canada).
The synthesis of 3-carboxyceph-3-em S-oxide 15 started
from 7-ACA by protection of the amino part (vide supra).
Then sulfide 2 was oxidised to the sulfoxide 3 with meta-
chloroperbenzoic acid in quantitative yield. Hydroxy acid 6
was obtained by enzymatic hydrolysis (cephalosporin acetyl
hydrolase) of the C10 acetate and the tert-butyl ester of 6
was prepared by treatment with the isourea derived from
(7R,7aR)-3-[(Acetyloxy)methyl]-6-oxo-7-[(2-phenylacetyl)amino]-
7,7a-dihydro-2H,6H-azeto[2,1-b][1,3]thiazine-4-carboxylic Acid (2):
To a solution of 7-ACA 1 (12.00 g, 44.12 mmol) in saturated aque-
ous NaHCO3 (300 mL) and acetone (100 mL) was added
phenylacetyl chloride (ca. 2 equivalents, ca. 6.0 mL) in two por-
tions. After 17 h stirring, the reaction mixture was acidified with
DCC and tert-butyl alcohol to give ester alcohol 9 in an concentrated HCl to pH 1.5 and extracted with CH2Cl2 (2 ϫ
250 mL) and the combined organic layers were washed with brine,
dried (MgSO4) and concentrated in vacuo. The residue was sus-
pended in diethyl ether and stirred for 17 h to remove phenylacetic
acid (by-product). The product was filtered off, washed with diethyl
ether and dried in vacuo. Phenylacetyl protected 7-ACA 2 was ob-
tained as an off-white solid (14.20 g, 83%) and was used without
any further purification. M.p. 168Ϫ171 °C (dec.). Ϫ [α]2D0 ϭ ϩ86
overall yield of 61%. Oxidation of the primary alcohol func-
tion at C10 to the corresponding formyl product 12 was
accomplished using IBX as the oxidant similar to the con-
version of 8 into 11, again in excellent yield. Gratifyingly,
this formyl compound 12 was readily oxidized to the carb-
oxylic acid by sodium chlorite in high yield. The sulfoxide
function has a stabilizing effect on this molecule as has been
demonstrated before.[24] Finally, reduction of sulfoxide 15
to sulfide 14 could be accomplished by treatment with
(c
ϭ 1.0, dioxane). Ϫ
1H NMR (100 MHz, CDCl3 and
[D6]DMSO): δ ϭ 2.07 (s, 3 H, CH3), 3.32 and 3.54 (qAB, J ϭ
15.0 Hz, 2 H, SCH2), 3.58 (s, 2 H, PhCH2), 4.84 and 5.08 (qAB,
acetyl chloride in DMF and a catalytic amount of tin(II) J ϭ 13.3 Hz, 2 H, CH2OAc), 4.95 (d, J ϭ 4.9 Hz, 1 H,
chloride analogous to Kaiser et al.[25] Thus, the above-men-
tioned detour to target compound 14 via the sulfoxide route
was indeed possible.
NHCHCHS), 5.77 (dd, J ϭ 4.8 Hz J ϭ 8.5 Hz, 1 H, NHCHCHS),
7.29 (m, 5 H, Ph-H), 8.18 (d, J ϭ 8.5 Hz, 1 H, NH), 9.64 (s, 1 H,
CO2 H). Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ 20.8 [OC(-
O)CH3], 25.7 (SCH2), 41.8 (PhCH2), 57.6 (CHNH), 59.3 (CHS),
62.9 (CH2OAc), 123.6 (ϭCCH2OAc) 126.5 (ϭCCO2 H), 126.7,
128.4, 129.2 and 136.0 (Ph-C), 163.0 (CϭO, lactam), 165.0 (CO2
H), 170.4 [OC(O)CH3], 171.2 [PhCH2C(O)]. Ϫ IR (KBr): ν˜ ϭ 3260
Conclusion
(broad, NH), 1782 (CϭO, lactam), 1748 (CϭO, acetyl), 1738 (Cϭ
In conclusion, starting from the readily available 7-ACA
O, acid), 1658 and 1535 (CϭO, amide), 1345 (CϪN), 1228 (CϪO,
acetyl) cmϪ1. Ϫ MS (FABϩ, NOBA): m/z (%) ϭ 413 (51) [M ϩ
Na]ϩ, 391 (18) [M ϩ H]ϩ, 331 (100) [M ϩ H Ϫ CO2CH3]ϩ.
1, we developed a convenient synthesis for some 3-carboxy-
cephems, namely 3-carboxyceph-2-em 13 and 3-carboxy-
ceph-3-em sulfide 14 and the corresponding sulfoxide 15 in
high overall yields. These 3-carboxy derivatives are valuable
compounds for further synthetic elaboration, to prepare
new types of antibiotics.
(7R,7aR)-3-[(Acetyloxy)methyl]-1,6-dioxo-7-[(2-phenylacetyl)-
amino]-1,6,7,7a-tetrahydro-2H-1λ4-azeto[2,1-b][1,3]thiazine-4-carb-
oxylic Acid (3): To a cooled (0 °C) suspension of phenylacetyl pro-
tected 7-ACA 2 (0.78 g, 2.00 mmol) in CH2Cl2 (50 mL) was added
1.5 equiv. of pre-dried MCPBA (0.26 g) in one portion. After addi-
tional stirring (1.5 h) the precipitate (white solid) was collected by
filtration, washed with CH2Cl2 (2 ϫ 25 mL) to remove MCBA,
and dried in vacuo. The crude sulfoxide 3 (0.80 g, 98%) was used
without any further purification. M.p. 197Ϫ198 °C (dec.). Ϫ
Experimental Section
1
General Remarks: 100 MHz H NMR spectra were recorded on a
1
Bruker AC 100 spectrometer and 300 MHz H NMR spectra and
[α]2D0
ϭ ϩ161 (c ϭ 0.87, H2O). Ϫ
1H NMR (300 MHz,
all 13C NMR spectra were recorded on a Bruker AC 300 using
[D6]DMSO): δ ϭ 2.02 (s, 3 H, CH3), 3.52 and 3.73 (qAB, J ϭ
3
Me4Si as internal standard. All coupling constants are given as J 14.4 Hz, 2 H, PhCH2), 3.56 and 3.88 (qAB, J ϭ 18.5 Hz, 2 H,
in Hz, unless indicated otherwise. Ϫ Melting points were measured
with a Reichert Thermopan microscope and are uncorrected. Ϫ IR J ϭ 4.2 Hz, 1 H, NHCHCHS), 5.81 (dd, J ϭ 4.2 Hz J ϭ 8.2 Hz,
spectra were recorded on a Bio-Rad FTS-25 instrument. Ϫ For 1 H, NHCHCHS), 7.21Ϫ7.31 (m, 5 H, Ph-H), 8.40 (d, J ϭ 8.2 Hz,
mass spectra a double focusing VG7070E mass spectrometer was 1 H, NH). Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ 20.8 [OC(-
SCH2), 4.59 and 5.19 (qAX, J ϭ 13.1 Hz, 2 H, CH2OAc), 4.86 (d,
used. Ϫ Elemental analyses were conducted on a Carlo Erba In-
O)CH3], 41.6 (PhCH2), 45.5 (SCH2), 58.4 (CH2OAc), 63.2 (CHS),
Eur. J. Org. Chem. 2001, 2529Ϫ2534
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R. Keltjens, S. K. Vadivel, E. de Vroom, A. J. H. Klunder, B. Zwanenburg
FULL PAPER
66.4 (CHS), 118.7 (ϭCCH2OAc) 126.1 (ϭCCO2H), 126.7, 128.5, 60.1 (CHS), 64.9 (CH2OH), 84.0 [C(CH3)3], 117.2 (SCHϭ), 124.3
129.3 and 136.0 (Ph-C), 162.3 (CϭO, lactam), 164.4 (CO2 H), 170.3 (ϭCCH2OH) 127.6, 129.0, 129.4 and 133.8 (Ph-C), 164.5 (CϭO
[OC(O)CH3], 171.2 [PhCH2C(O)]. Ϫ IR (KBr): ν˜ ϭ 3298 (broad,
NH), 1775 (CϭO, lactam), 1742 (CϭO, acetyl), 1723 (CϭO, acid),
lactam), 166.5 (CHCO2tBu), 171.2 [PhCH2C(O)]. Ϫ IR (KBr): ν˜ ϭ
3431 (broad, OH), 3298 (broad, NH), 1770 (CϭO, lactam), 1732
1658 and 1527 (CϭO, amide), 1339 (CϪN), 1222 (CϪO, acetyl), (CϭO, ester), 1660 and 1535 (CϭO, amide), 1369 (CϪN), 1151
1035 (SϭO) cmϪ1. Ϫ MS (FABϩ, NOBA): m/z (%) ϭ 429 (13) [M (OϪC, ester) cmϪ1. Ϫ MS (FABϩ, NOBA): m/z (%) ϭ 427 (21) [M
ϩ Na]ϩ, 407 (3) [M ϩ H]ϩ, 347 (12) [M ϩ HϪCOCH3]ϩ, 514 ϩ Na]ϩ, 404 (5) [Mϩ], 331 (35) [M ϩ H Ϫ C4H8 Ϫ H2O]ϩ, 176
(100).
(57), 57 (100). Ϫ C20H24N2O5S (404.49): calcd. C 59.39, H 5.98, N
6.93, S 7.93; found C 59.39, H 5.97, N 6.83, S 8.07.
tert-Butyl (4S,7R,7aR)-3-[(Acetyloxy)methyl]-6-oxo-7-[(2-phenyl-
acetyl)-amino]-7,7a-dihydro-4H,6H-azeto[2,1-b][1,3]thiazine-4- tert-Butyl (7R,7aR)-3-(Hydroxymethyl)-6-oxo-7-[(2-phenylacetyl)-
carboxylate (4): DCC (5.81 g, 28.16 mmol) was added to a cooled amino]-7,7a-dihydro-2H,6H-azeto[2,1-b][1,3]thiazine-4-carb-
(Ϫ30 °C) and stirred suspension of phenylacetyl protected 7-ACA
oxylate (8): Phenylacetyl protected 7-ACA 2 (4.00 g, 10.26 mmol)
2 (10.00 g, 25.6 mmol), tert-butyl alcohol (5 mL) and DMAP was dissolved in water and the pH was set to 7.0 with 0.6  NaOH.
(200 mg) in CH2Cl2 (200 mL) under nitrogen. The reaction mixture After addition of immobilized cephalosporin acetyl hydrolase
was stirred for 1 h at 0 °C and for a further 15 h at room temper-
ature. After removal of DCU by filtration, HCl (2 ⁾ was added to
the filtrate. Crude tert-butyl ester was obtained by extraction with
(8.00 g ‘‘wet’’ enzyme) the pH was maintained at pH 7.0 by addi-
tion of 0.1  NaOH (pH stat conditions). After completion (4Ϫ6
h) the enzyme was recovered by filtration. The filtrate was acidified
CH2Cl2 (3 ϫ 200 mL), washing with saturated NaHCO3 (1 ϫ to pH 1.8 after cooling to 0 °C. The precipitate formed was col-
200 mL) and brine (1 ϫ 200 mL), drying (MgSO4), and concentra-
lected by filtration and dried in vacuo or extracted (3 ϫ 150 mL)
tion in vacuo. Crystallization from ethyl acetate/heptane, after
with ethyl acetate. The combined organic layers were washed with
treatment with active carbon, gave pure tert-butyl ester 4 with the water (2 ϫ 50 mL) and brine, dried (MgSO4), and concentrated in
2
∆
double bond, as white needles (10.10 g, 88%). M.p. 227Ϫ229
vacuo. The crude product 5 was dissolved in dry THF. At room
temperature the carboxylic acid was esterified with isourea derived
°C, [α]2D0 ϭ ϩ409 (c ϭ 0.53, acetone). Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 1.47 [s, 9 H, C(CH3)3], 2.06 [s, 3 H, C(O)CH3], 3.64 from tert-butyl alcohol and DCC (4 equiv.). After stirring for 17 h,
(s, 2 H, PhCH2), 4.53 and 4.71 (qAB, J ϭ 12.7 Hz, 2 H, CH2OAc), DCU was removed by filtration. After addition 2  HCl, the filtrate
4.87 (s, 1 H, CHCO2tBu), 5.26 (d, J ϭ 4.0 Hz, 1 H, NHCHCHS), was extracted with CH2Cl2 (3 ϫ 100 mL). The combined organic
5.65 (dd, J ϭ 4.0 Hz J ϭ 8.7 Hz, 1 H, NHCHCHS), 6.23 (d, J ϭ
8.7 Hz, 1 H, NH), 6.34 (s, 1 H, SCHϭ), 7.26Ϫ7.40 (m, 5 H, Ph-
layers were extracted with saturated NaHCO3 (1 ϫ 75 mL) and
brine (1 ϫ 75 mL), dried (MgSO4) providing tert-butyl ester 8 after
H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 20.8 [OC(O)CH3], 27.9 column chromatography (silica gel, heptane/ethyl acetate 1:2) as a
[C(CH3)3], 43.3 (PhCH2), 50.6 (CHCO2tBu) 53.4 (CHNH), 60.2 white solid (2.10 g, 61%). Ϫ M.p. 174Ϫ176 °C (dec.). Ϫ [α]2D0
(CHS), 65.4 (CH2OH), 84.0 [C(CH3)3], 119.4 (SCHϭ), 121.2 (ϭ ϩ83 (c ϭ 0.87, acetone). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.66
CCH2OAc) 127.6, 129.1, 129.4 and 133.6 (Ph-C), 164.2 (CϭO, lac- (s, 9 H, C(CH3)3], 3.00 (br. s, 1 H, OH), 3.49 and 3.53 (qAB, J ϭ
tam), 165.9 (CHCO2tBu), 170.4 [OC(O)CH3], 171.0 [PhCH2C(O)]. 18.6 Hz, 2 H, SCH2), 3.61 and 3.65 (qAB, J ϭ 15.9 Hz, 2 H,
ϭ
Ϫ IR (KBr): ν˜ ϭ 3246 (broad, NH), 3058 (CH, phenyl), 1782 (Cϭ
O, lactam), 1736 (CϭO, ester and acetyl), 1649 and 1560 (CϭO,
PhCH2), 3.86 (dd, J ϭ 5.0 Hz J ϭ 12.6 Hz, 1 H, CH2OH), 4.46 (d,
J ϭ 12.6 Hz, 1 H, CH2OH), 4.89 (d, J ϭ 4.9 Hz, 1 H, NHCHCHS),
5.83 (dd, J ϭ 4.9 Hz J ϭ 9.1, 1 H, NHCHCHS), 6.53 (d, J ϭ
amide), 1387 (CϪN), 1218 (CϪO, acetyl) 1153 (CϪO, ester) cmϪ1
.
Ϫ MS (CIϩ): m/z (%) ϭ 446 (5) [Mϩ], 405 (3) [M ϩ H Ϫ COCH3]ϩ, 9.1 Hz, 1 H, NH), 7.25Ϫ7.38 (m, 5 H, Ph-H). Ϫ 13C NMR
345 (14) [M ϩ H Ϫ COCH3 Ϫ C4H8]ϩ, 331 (60), 176 (72), 216
(95), 91 (100). HRMS (EI, m/z): 446.15036 (calcd. for 57.1 (CH2OH), 59.0 (CHNH), 61.9 (CHS), 84.0 [C(CH3)3], 126.5,
(75 MHz, CDCl3): δ ϭ 25.6 (SCH2), 27.3 [C(CH3)3], 43.1 (PhCH2),
Ϫ
C22H26N2O6S: 446.15115).
127.6, 129.1, 129.4, 129.9, 133.7 (ϭCCO2tBu, ϭCCH2OH and Ph-
C), 161.4 (CO2tBu), 164.6 (CϭO, lactam), 171.3 (PhCH2C(O)]. Ϫ
IR (KBr): ν˜ ϭ 3409 (broad, OH), 3298 (broad, NH), 1756 (CϭO,
lactam), 1709 (CϭO, ester), 1661 and 1536 (CϭO, amide), 1367
(CϪN), 1163 (CϪO, ester) cmϪ1. Ϫ MS (FABϩ, NOBA): m/z
(%) ϭ 427 (44) [M ϩ Na]ϩ, 405 (17) [M ϩ H]ϩ, 387 (42) [M ϩ
H Ϫ H2O]ϩ, 331 (49) [M ϩ H Ϫ C4H8 Ϫ H2O]ϩ, 178 (100). Ϫ
C20H24N2O5S (404.49): calcd. C 59.39, H 5.98, N 6.93, S 7.93;
found C 59.36, H 6.03, N 6.87, S 7.93.
tert-Butyl (4S,7R,7aR)-3-(Hydroxymethyl)-6-oxo-7-[(2-phenylacetyl)-
amino]-7,7a-dihydro-4H,6H-azeto[2,1-b][1,3]thiazine-4-carboxylate
(7): Sodium hydroxide (0.90 g, 22.50 mmol) in methanol (30 mL)
was added under nitrogen to a cooled (Ϫ30 °C) and stirred solution
of triple protected 7-ACA 4 (5.00 g, 0.011 mol) in methanol
(360 mL). The reaction mixture was stirred between Ϫ30 and Ϫ20
°C for 4Ϫ5 h until TLC analysis (ethyl acetate/hexane 1:1) showed
completion of the reaction. The reaction mixture was then poured
into diluted HCl solution and extracted with CH2Cl2 (3 ϫ 75 mL).
The combined organic layers were washed with brine (1 ϫ 50 mL),
water (1 ϫ 50 mL), dried (MgSO4), and concentrated in vacuo af-
tert-Butyl (7R,7aR)-3-(Hydroxymethyl)-1,6-dioxo-7-[(2-phenylacetyl)-
amino]-1,6,7,7a-tetrahydro-2H-1λ4-azeto[2,1-b][1,3]thiazine-4-carb-
oxylate (9): The procedure as described for the preparation of the
fording crude alcohol 7 as a yellow-orange foam (4.44 g, 98%). An sulfide analogue was followed using phenylacetyl protected 7-ACA-
analytical sample was obtained after column chromatography (sil-
sulfoxide 3 (1.50 g, 3.69 mmol), immobilized cephalosporin acetyl
hydrolase (4.0 g ‘‘wet’’ enzyme) and isourea (4 equiv.) derived from
tert-butyl alcohol and DCC. Workup after 4Ϫ6 h followed by puri-
ica gel, ethyl acetate/heptane 2:1). M.p. 85Ϫ87 °C (dec.). Ϫ [α]2D0
ϭ
1
ϩ471 (c ϭ 0.525, acetone). Ϫ H NMR (300 MHz, CDCl3): δ ϭ
1.48 [s, 9 H, C(CH3)3], 2.46 (br. s, 1 H, CH2OH), 3.63 (s, 2 H, fication via chromatography (silica gel, ethyl acetate) afforded tert-
PhCH2), 4.12 and 4.21 (dqAB, JAB ϭ 13.4 Hz J ϭ 5.5 Hz, 2 H,
butyl ester 9 as a white solid (0.96 g, 62%). M.p. 198Ϫ199 °C (dec.).
4
CH2OH,), 4.92 (d, J ϭ ഠ1.0 Hz, 1 H, CHCO2tBu), 5.22 (d, J ϭ Ϫ [α]2D0 ϭ ϩ87 (c ϭ 0.51, acetone). Ϫ 1H NMR (300 MHz,
4.0 Hz, 1 H, NHCHCHS), 5.61 (dd, J ϭ 4.0 Hz J ϭ 8.7 Hz, 1 H, [D6]DMSO): δ ϭ 1.49 [s, 9 H, C(CH3)3], 3.53 and 3.85 (qAB, J ϭ
4
NHCHCHS), 6.23 (d, J ϭ ഠ1.0 Hz, 1 H, SCH), 6.27 (br. s, 1 H, 18.6 Hz, 2 H, SCH2), 3.49 and 3.75 (qAB, J ϭ 14.1 Hz, 2 H,
NH), 7.26Ϫ7.38 (m, 5 H, Ph-H), 13C NMR (75 MHz, CDCl3): δ ϭ PhCH2), 4.07 and 4.42 (dqAB, JAB ϭ 13.9 Hz J ϭ 5.6 Hz, 2 H,
27.9 [C(CH3)3], 43.2 (PhCH2), 50.7 (CHCO2tBu) 53.6 (CHNH), CH2OH), 4.83 (d, J ϭ 4.5 Hz, 1 H, NHCHCHS), 5.13 (t, J ϭ
2532
Eur. J. Org. Chem. 2001, 2529Ϫ2534

A New Convenient Synthesis of 3-Carboxycephems
FULL PAPER
5.6 Hz, 1 H, CH2OH) 5.87 (dd, J ϭ 4.5 Hz J ϭ 8.4 Hz, 1 H,
tert-Butyl (7R,7aR)-3-Formyl-1,6-dioxo-7-[(2-phenylacetyl)-
NHCHCHS), 7.23Ϫ7.31 (m, 5 H, Ph-H), 8.34 (d, J ϭ 8.4 Hz, 1 H, amino]-1,6,7,7a-tetrahydro-2H-1λ4-azeto[2,1-b][1,3]thiazine-
NH). Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ 27.7 [C(CH3)3], 41.7 4-carboxylate (12): This compound was prepared from alcohol 9
(SCH2), 45.5 (PhCH2), 58.2 (CH2OH), 60.4 (CHNH), 66.4 (CHS),
(0.42 g, 1.00 mmol) in the same way as described for the synthesis
82.6 [C(CH3)3], 123.3 (ϭCCO2tBu), 125.7 (ϭCCH2OH), 126.7, of 3-formylceph-2-em 10. Purification by chromatography (silica
128.5, 129.3, and 136.4 (Ph-C), 160.2 (CO2tBu), 164.2 (CϭO, lac- gel, ethyl acetate/heptane 2:1) afforded 12 as a white solid (0.40 g,
tam), 171.2 [PhCH2C(O)]. Ϫ IR (KBr): ν˜ ϭ 3509 (broad, OH), 95%). Ϫ M.p. 175Ϫ176 °C (dec.). Ϫ [α]2D0 ϭ Ϫ153 (c ϭ 0.48, acet-
1
3229 (broad, NH), 1782 (CϭO, lactam), 1695 (CϭO, ester), 1661 one). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.58 [s, 9 H, C(CH3)3],
and 1541 (CϭO, amide), 1327 (CϪN), 1159 (CϪO, ester), 1031 2.85 (dd, J ϭ 18.4 Hz 4J ϭ 1.6 Hz, 1 H, SCH2), 3.63 (s, 2 H,
(SϭO) cmϪ1. Ϫ MS (FABϩ, NOBA): m/z (%) ϭ 443 (18) [M ϩ PhCH2), 4.40 (d, J ϭ 18.4 Hz, 1 H, SCH2), 4.47 (dd, J ϭ 5.2 Hz
Na]ϩ, 421 (5) [M ϩ H]ϩ, 403 (10), 387 (10), 365 (12), 347 (38), 225 4J ϭ 1.6 Hz, 1 H, NHCHCHS), 6.16 (dd, J ϭ 5.2 Hz J ϭ 9.9 Hz,
(48), 91 (92), 57 (100). Ϫ C20H24O6N2S (420.49): calcd. C 57.13, H 1 H, NHCHCHS), 6.91 (d, J ϭ 9.9 Hz, 1 H, NH), 7.25Ϫ7.37 (m,
5.75, N 6.66; found C 56.73, H 5.71, N 6.62.
5 H, Ph-H), 9.97 (s, 1 H, CHO). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ 27.7 [C(CH3)3], 41.4 (SCH2), 43.1 (PhCH2), 60.0 (CHNH),
67.6 (CHS), 86.3 [C(CH3)3], 116.5 (ϭCCHO), 127.6, 129.0, 129.3
and 133.6 (Ph-C), 139.9 (ϭCCO2tBu), 158.2 (CO2tBu), 164.5 (Cϭ
O, lactam), 171.3 [PhCH2C(O)], 188.4 (CHO). Ϫ IR (KBr): ν˜ ϭ
3324 (broad, NH), 1800 (CϭO, lactam), 1705 (CϭO, ester), 1672
and 1520 (CϭO, amide), 1370 (CϪN), 1153 (CϪO, ester), 1025
(SϭO) cmϪ1. Ϫ MS (FABϩ, NOBA): m/z (%) ϭ 441 (2) [M ϩ
tert-Butyl (4S,7R,7aR)-3-Formyl-6-oxo-7-[(2-phenylacetyl)-
amino]-7,7a-dihydro-4H,6H-azeto[2,1-b][1,3]thiazine-4-carb-
oxylate (10): To a stirred solution of iodoxy benzoic acid (1.40 g,
5.00 mmol) in DMSO (8 mL) was added a solution of alcohol 7
(1.00 g, 2.48 mmol) in THF (3 mL) over a period of 3 h. The reac-
tion mixture was stirred for an additional 30 h at room temper-
ature. Then the reaction mixture was extracted with ethyl acetate,
washed with water (3 ϫ 15 mL), brine (1 ϫ 15 mL), dried with
MgSO4, and concentrated in vacuo. The crude product was puri-
fied by column chromatography (silica gel, ethyl acetate/hexane 3:7)
to furnish aldehyde 10 (0.81 g, 81%) as a colorless solid. Ϫ M.p.
146Ϫ148 °C (dec.). Ϫ [α]2D0 ϭ ϩ679 (c ϭ 0.30, acetone). Ϫ 1H
NMR (300 MHz, CDCl3): δ ϭ 1.44 [s, 9 H, C(CH3)3], 3.65 (s, 2
H, PhCH2), 5.27 (s, 1 H, CHCO2tBu), 5.30 (d, J ϭ 3.9 Hz, 1 H,
NHCHCHS), 5.55 (dd, J ϭ 3.9 Hz J ϭ 7.6 Hz, 1 H, NHCHCHS),
6.22 (d, J ϭ 7.6 Hz, 1 H, NH), 7.26Ϫ7.40 (m, 5 H, Ph-H), 7.43 (s,
1 H, SCH), 9.25 (s, 1 H, CHO). Ϫ 13C NMR (75 MHz, CDCl3):
Na]ϩ, 419 (2) [M ϩ H]ϩ, 363 (80) [M ϩ H Ϫ C4H8]ϩ, 91 (100)
ϩ
[PhCH2
]
Ϫ
HRMS (FAB, m/z): 441.1059 (calcd. for
C20H22N2O6SNa: 441.1096).
(4S,7R,7aR)-4-(tert-Butoxycarbonyl)-6-oxo-7-[(2-phenylacetyl)-
amino]-7,7a-dihydro-4H,6H-azeto[2,1-b][1,3]thiazine-
3-carboxylic Acid (13): Aldehyde 10 (0.80 g, 1.99 mmol) was dis-
solved in THF (28 mL) and cyclohexene (8 mL) was added. After
cooling 0 °C a mixture of KH2PO4 (1.50 g) and NaClO2 (1.20 g)
in water (28 mL) was added. The reaction mixture was allowed to
warm up to room temperature slowly and then stirred overnight.
The reaction mixture was acidified with 2  HCl and the THF was
removed in vacuo. The aqueous layer was extracted with ethyl acet-
ate (3 ϫ 75 mL). The combined organic layer was washed with
brine (1 ϫ 50 mL), dried (MgSO4), and concentrated under re-
duced pressure. The crude residue was washed with ether to obtain
acid 13 (0.77 g, 93%). An analytically pure sample could be ob-
tained by column chromatography (silica gel, ethyl acetate/hexane
1:1). Ϫ M.p. 178Ϫ180 °C (dec.). Ϫ [α]2D0 ϭ ϩ535 (c ϭ 1.0, acetone).
δ
ϭ 27.8 [C(CH3)3], 43.1 (PhCH2), 49.8 (CHCO2tBu) 53.9
(CHNH), 60.4 (CHS), 83.7 [C(CH3)3], 116.1 (ϭCCO2 H), 127.7,
129.1, 129.4 and 133.5 (Ph-C), 138.0 (SCH) 163.9 (CϭO, lactam),
165.7 (CHCO2tBu), 167.5 (CO2 H), 171.5 [PhCH2C(O)]. Ϫ IR
(KBr): ν˜ ϭ 3265 (broad, NH), 1768 (CϭO, lactam), 1733 (CϭO,
ester), 1667 and 1544 (CϭO, amide), 1369 (CϪN), 1152 (OϪC,
ester) cmϪ1. Ϫ MS (FABϩ, NOBA): m/z (%) ϭ 425 (30) [M ϩ
Na]ϩ, 403 (11) [M ϩ H]ϩ, 347 [M ϩ H Ϫ C4H8]ϩ, 178 (100). Ϫ
C20H22N2O5S (402.47): calcd. C 59.69, H 5.51, N 6.96 S 7.97;
found C 59.73, H 5.59, N 6.93, S 7.97.
1
Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.44 [s, 9 H, C(CH3)3], 3.64
(s, 2 H, PhCH2), 5.15 (d, J ϭ 3.9 Hz, 1 H, NHCHCHS), 5.21 (s, 1
tert-Butyl (7R,7aR)-3-Formyl-6-oxo-7-[(2-phenylacetyl)amino]-
H, CHCO2tBu), 5.55 (dd,
J ϭ 3.9 Hz J ϭ 7.8 Hz, 1 H,
7,7a-dihydro-2H,6H-azeto[2,1-b][1,3]thiazine-4-carboxylate
(11):
NHCHCHS), 6.61 (d, J ϭ 7.8 Hz, 1 H, NH), 7.25Ϫ7.35 (m, 5 H,
Ph-H), 7.74 (s, SCH). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 27.8
[C(CH3)3], 43.1 (PhCH2), 49.8 (CHCO2tBu) 53.9 (CHNH), 60.4
(CHS), 83.7 [C(CH3)3], 116.1 (ϭCCO2 H), 127.7, 129.1, 129.4 and
133.5 (Ph-C), 138.0 (SCH) 163.9 (CϭO, lactam), 165.7
(CHCO2tBu), 167.5 (CO2 H), 171.5 [PhCH2C(O)]. Ϫ IR (KBr):
ν˜ ϭ 3326 (broad, NH), 1805 (CϭO, lactam), 1736 (CϭO, ester),
1678 and 1537 (CϭO, amide), 1640 (CϭO, acid), 1389 (CϪN) 1162
(CϪO, ester) cmϪ1. Ϫ MS (FABϩ, NOBA): m/z (%) ϭ 441 (18) [M
ϩ Na]ϩ, 419 (8) [M ϩ H]ϩ, 385 (9), 363 (32), 178 (100), 274 (100).
Ϫ C20H22N2O6S (418.47): calcd. C 57.40, H 5.30, N 6.69; found C
57.56, H 5.35, N 6.65.
This compound was prepared from alcohol 8 (0.57 g, 1.41 mmol)
in the same way as described for the synthesis of 3-formylceph-2-
em 10 (0.54 g, 96%). An analytical sample was obtained by column
chromatography (silica gel, ethyl acetate/heptane 1:1) followed by
re-crystallization (diethyl ether). Ϫ M.p. 146Ϫ148 °C (dec.). Ϫ [α]D20
ϭ ϩ152 (c ϭ 0.51, acetone). Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 1.56 [s, 9 H, C(CH3)3], 3.24 and 3.94 (qAB, J ϭ 18.3 Hz, 2 H,
SCH2), 3.63 and 3.67 (qAB, J ϭ 16.0 Hz, 2 H, PhCH2), 4.99 (d,
J ϭ 5.4 Hz, 1 H, NHCHCHS), 5.95 (dd, J ϭ 5.4 Hz J ϭ 9.2 Hz,
1 H, NHCHCHS), 6.33 (d, J ϭ 9.2 Hz, 1 H, NH), 7.25Ϫ7.40 (m,
5 H, Ph-H), 9.80 (s, 1 H, CHO). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ 22.1 (SCH2), 27.7 [C(CH3)3], 43.2 (PhCH2), 58.9 (CHNH),
59.8 (CHS), 85.8 [C(CH3)3], 122.4 (ϭCCHO), 127.7, 129.2, 129.3 (7R,7aR)-4-(tert-Butoxycarbonyl)-6-oxo-7-[(2-phenylacetyl)amino]-
and 133.5 (Ph-C), 140.2 (ϭCCO2tBu), 159.0 (CO2tBu), 164.7 (Cϭ 7,7a-dihydro-2H,6H-azeto[2,1-b][1,3]thiazine-3-carboxylic Acid
O, lactam), 171.1 [PhCH2C(O)], 187.9 (CHO). Ϫ IR (KBr): ν˜ ϭ (14): A solution of sulfoxide 15 (0.35 g, 0.73 mmol) in dry DMF
3334 (broad, NH), 1795 (CϭO, lactam), 1705 (CϭO, ester), 1668 (3 mL) was treated with tin(II) chloride (0.48 g, 2.75 mmol) and an
and 1518 (CϭO, amide), 1373 (CϪN), 1226 and 1161 (CϪO, ester)
excess of acetyl chloride (1.5 mL) at 0 °C for 2 h. After removal of
cmϪ1. Ϫ MS (FABϩ, NOBA): m/z (%) ϭ 425 (18) [M ϩ Na]ϩ, 403 excess acetyl chloride (in vacuo) ethyl acetate and water were ad-
(13) [M ϩ H]ϩ, 347 (28) [M ϩ H Ϫ C4H8]ϩ, 176 (100). Ϫ ded. Extraction with ethyl acetate (2 ϫ 10 mL), drying (MgSO4),
C20H22N2O5S (402.47): calcd. C 59.69, H 5.51, N 6.96 S 7.97; and concentration in vacuo afforded the crude sulfide in nearly
found C 59.51, H 5.53, N 6.88, S 7.94.
quantitative yield. Purification by column chromatography (silica
Eur. J. Org. Chem. 2001, 2529Ϫ2534
2533

R. Keltjens, S. K. Vadivel, E. de Vroom, A. J. H. Klunder, B. Zwanenburg
FULL PAPER
gel, ethyl acetate/acetone 1:1) gave sulfide 14 (0.185 g, 55%) as a
[1]
[2]
white solid. An analytically pure sample was obtained by recrys-
D. O. Spry, J. Chem. Soc., Chem. Commun. 1974, 1012Ϫ1013.
D. O. Spry, United States Patent 3,953,436 (Eli Lilly and Co.)
1976.
D. O. Spry, United States Patent 4,001,226 (Eli Lilly and Co.)
1977.
D. O. Spry, United States Patent 4,012,380 (Eli Lilly and Co.)
1977.
H. Peter, B. Müller, H. Bickel, Helv. Chim. Acta 1975, 58,
2450Ϫ2469.
H. Peter, B. Müller, W. Sibral, H. Bickel, Germany Patent
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T. Matsuo, I. Sugahara, H. Masuya, T. Miki, Japan Patent
52083868 (Takeda Ltd.) 1977.
A. Reliquet, J. C. Meslin, F. Reliquet, H. Quiniou, Tetrahedron
1988, 44, 1107Ϫ1115.
M. Bakasse, A. Reliquet, F. Reliquet, G. Duguay, H. Quiniou,
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G. M. Whitesides, C.-H. Wong, Angew. Chem. 1985, 97,
617Ϫ638; Angew. Chem. Int. Ed. Engl. 1985, 24, 617.
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H. Waldmann, A. Heuser, A. Reidel, Synlett 1994, 65Ϫ67.
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345Ϫ348.
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der Marel, J. H. van Boom, Liebigs Ann./Recueil 1997,
1215Ϫ1220.
tallisation from diethyl ether. Ϫ M.p. 165Ϫ167 °C (dec.). Ϫ [α]2D0
ϭ
Ϫ58.8 (c ϭ 0.32, acetone). Ϫ 1H NMR (300 MHz, [D6]acetone):
δ ϭ 1.51 [s, 9 H, C(CH3)3], 3.57 and 3.86 (qAB, J ϭ 17.8 Hz, 2 H,
SCH2), 3.67 and 3.68 (qAB, J ϭ 14.3 Hz, 2 H, PhCH2), 5.17 (d,
J ϭ 5.1 Hz, 1 H, NHCHCHS), 5.90 (dd, J ϭ 5.1 Hz J ϭ 8.9 Hz,
1 H, NHCHCHS), 7.24Ϫ7.38 (m, 5 H, Ph-H), 8.17 (d, J ϭ 8.9 Hz,
1 H, NH). Ϫ 13C NMR (75 MHz, [D6]acetone): δ ϭ 25.0 (SCH2),
27.8 [C(CH3)3], 43.0 (PhCH2), 60.0 and 60.8 (CHNH and CHS),
83.6 [C(CH3)3], 110.7 (ϭCCO2 H), 127.5, 129.1, 130.0 and 136.4
(Ph-C), 136.6 (ϭCCO2tBu), 161.7 (CO2tBu), 165.3 (CϭO, lactam),
166.3 (CO2 H), 171.6 [PhCH2C(O)]. Ϫ IR (KBr): ν˜ ϭ 3298 (broad,
NH), 2978 (COOϪH), 1795 (CϭO, lactam), 1730 (CϭO, ester),
1716 (CϭO, acid), 1684 and 1523 (CϭO, amide) 1369 (CϪN), 1155
(CϪO, ester) cmϪ1. Ϫ MS (FABϩ, NOBA): m/z (%) ϭ 441 (14) [M
ϩ Na]ϩ, 419 (16) [M ϩ H]ϩ, 363 (52) [M ϩ H Ϫ C4H8]ϩ, 176
(100). Ϫ C20H22N2O6S (418.47): calcd. C 57.40, H 5.30, N 6.69;
found C 57.29, H 5.30, N 6.54.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
(7R,7aR)-4-(tert-Butoxycarbonyl)-1,6-dioxo-7-[(2-phenylacetyl)-
amino]-1,6,7,7a-tetrahydro-2H-1λ4 -azeto[2,1-b][1,3]thi-
azine-3-carboxylic Acid (15): This compound was prepared from
aldehyde 12 (0.78 g, 1.86 mmol) in the same way as described for
the synthesis of 3-carboxyceph-2-em 13. Yield after purification
(0.65 g, 80%). M.p. 163Ϫ165 °C (dec.). Ϫ [α]2D0 ϭ 9.80 (c ϭ 0.49,
acetone). Ϫ 1H NMR (300 MHz, [D6]acetone): δ ϭ 1.52 [s, 9 H,
C(CH3)3], 3.44 (dd, J ϭ 18.1 Hz 4J ϭ 1.8 Hz, 1 H, SCH2), 3.63
(qAB, J ϭ 14.6 Hz, 2 H, PhCH2), 4.26 (d, J ϭ 18.1 Hz, 1 H,
[13]
[14]
[15]
[16]
4
SCH2), 4.89 (dd, J ϭ 5.1 Hz J ϭ 1.6 Hz, 1 H, NHCHCHS), 6.12
[17]
[18]
M. Valencic, T. van der Does, E. de Vroom, Tetrahedron Lett.
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J. Chem. Soc. 1965, 5015Ϫ5031.
(d, J ϭ 5.1 Hz, 1 H, NHCHCHS), 7.25Ϫ7.40 (m, 5 H, Ph-H). Ϫ
13C NMR (75 MHz, [D6]acetone): δ ϭ 27.8 [C(CH3)3], 43.1
(SCH2), 44.8 (PhCH2), 60.3 (CHNH), 68.1 (CHS), 83.9 [C(CH3)3],
119.7 (ϭCCO2 H), 127.6, 129.3, 130.1 and 136.4 (Ph-C), 136.6 (ϭ
CCO2tBu), 161.1 (CO2tBu), 165.5 (CϭO, lactam), 167.9 (CO2 H),
172.6 [PhCH2C(O)]. Ϫ IR (KBr): ν˜ ϭ 3332 (broad, NH), 2980 and
2927 (COOϪH), 1793 (CϭO, lactam), 1729 (CϭO, ester), 1689
(CϭO, acid), 1657 and 1523 (CϭO, amide) 1380 (CϪN), 1215
(CϪO, ester), 1039 (SϭO) cmϪ1. Ϫ MS (FABϩ, NOBA): m/z (%) ϭ
457 (5) [M ϩ Na]ϩ, 434 (7) [Mϩ], 393 (13) [M ϩ NaϪC4H8]ϩ, 379
(14) [M ϩ H Ϫ C4H8]ϩ, 57 (100). Ϫ HRMS (FAB, m/z): 457.0984
(calcd. for C20H22N2O7SNa: 457.1045).
[19]
E. van Heyningen, C. N. Brown, J. Med. Chem. 1965, 8,
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Acknowledgments
We thank DSM Life Science Group (Delft, The Netherlands) and
the Dutch Ministry of Economical Affairs (Senter) for their finan-
cial support.
Received December 7, 2000
[O00627]
2534
Eur. J. Org. Chem. 2001, 2529Ϫ2534