A total synthesis of (1R,5R)-3-phenylmethyl-4-thia-2,6-diazabicyclo [3.2.0]hept-2-en-7-one, a useful intermediate for the preparation of penem and cepham derivatives

Article abstract of DOI:10.1055/s-2000-6260

The preparation of the thiazoline (1R,5R)-3-phenylmethyl-4-thia-2,6- diazabicyclo [3.2.0]hept-2-en-7-one (1) is presented. This compound, which has been extensively used as an intermediate for the synthesis of penems and cephams, has been obtained starting from a C-4 unsubstituted azetidinone by means of facile processes while chirality has been obtained through enzymatic resolution.

Full text of DOI:10.1055/s-2000-6260

PAPER
289
A Total Synthesis of (1R, 5R)-3-Phenylmethyl -4-thia-2,6-diazabicyclo
[3.2.0]hept-2-en-7-one, a Useful Intermediate for the Preparation of Penem
and Cepham Derivatives
Gianfranco Cainelli,* Daria Giacomini,* Paola Galletti
Dipartimento di Chimica ‘G. Ciamician’, Università di Bologna, Via Selmi 2, 40126 BO, Italy
Fax +39(051)2099456; E-mail: cainelli@ciam.unibo.it; giacomin@ciam.unibo.it
Received 28 July 1999; revised 30 September 1999
Abstract: The preparation of the thiazoline (1R,5R)-3-phenylmeth-
yl-4-thia-2,6-diazabicyclo [3.2.0]hept-2-en-7-one (1) is presented.
This compound, which has been extensively used as an intermediate
for the synthesis of penems and cephams, has been obtained starting
from a C-4 unsubstituted azetidinone by means of facile processes
while chirality has been obtained through enzymatic resolution.
Key words: antibiotics, b-lactams, cycloaddition, enzymes, kinetic
resolution
Scheme 1
Penicillins and cephalosporins represent one of the most
important groups of antibiotics. Even though many other
antimicrobial agents have been isolated since their discov-
ery, they are still the pharmaceutical of choice for a great
variety of infectious diseases and new derivatives are be-
ing prepared continuously.1
Our strategy for the total synthesis of 1 is shown in
Scheme 2. The direct precursor has been identified as the
thioamide 2, which can furnish target 1 through nucleo-
philic attack of the sulfur atom, thus exploiting the good
leaving ability of the acetoxy function at C-4. Thioamide
2 can in turn be obtained from the corresponding amide 3,
where the acetoxy group can be introduced starting from
a 3-amino-b-lactam 4. Even compound 3 is an interesting
intermediate in the total synthesis of cephalosporins and
penicillins.9
Few total syntheses of b-lactam antibiotics have been re-
ported in the literature.2 Generally, b-lactam compounds
are obtained through semisynthetic approaches that ex-
ploit the intermediate products obtained by the degrada-
tion of biosynthetic Penicillin G and V or Cephalosporin
C. With this methodology, i.e. by opening and recon-
structing the thiazolidine ring of penicillins or refunction-
alizing the dihydrothiazine ring of cephalosporins, many
important semisynthetic approaches to b-lactam antibiot-
ics have been realized. Both the starting material and the
target have bicyclic b-lactam structures, and the success
of this approach rests on the low-cost and ready availabil-
ity of the intermediates.
One of the synthons used is the thiazoline-azetidinone
(1R,5R)-3-phenylmethyl-4-thia-2,6-diazabicyclo[3.2.0]
hept-2-en-7-one (1), derived from penicillin G.3 The
chemical structure of 1 is particularly attractive because of
the correct functionalization and natural stereochemistry
at the C-1 and C-5 bonds. It has been used, together with
its 3-phenoxymethyl-analog,4 to prepare several penams,
penems, oxopenams and cephams.5 As an example, the
thiazoline ring of 1 is readily opened to give the corre-
sponding cis 4-mercaptoazetidin-2-one,6 which easily un-
dergoes base-induced 1,4-addition to α-halo-α,β-
unsaturated esters affording penam derivatives.7
Scheme 2
The key step is to obtain the two stereogenic centers at C-
1 and C-5 in the thiazolidine ring in high optical purity.
Among the possible synthetic solutions, we decided to use
facile racemic processes with inexpensive starting materi-
als and to obtain the natural configuration through a kinet-
ic enzymatic resolution. The required cis junction of the
thiazoline ring will follow as a consequence of the steric
ring tension in the bicyclic system.
In the context of our ongoing interest in the field of b-lac-
tams,8 we decided to develop a total synthetic approach to
penicillin and cephalosporin derivatives through the full
chemical synthesis of compound 1.
The preparation of racemic 3-aminoazetidin-2-one 4,
which represents the first step in the synthesis, was real-
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290
G. Cainelli et al.
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ized by means of the Staudinger reaction,10 by treating the deprotection procedure,13 could be performed at various
aminoketene derived from the acyl chloride 5 with the ap- stages of the synthesis. However, at this stage it was easy
propriate formaldimine obtained from hexahydro- to recover the product from the reaction mixture by simple
triazine11 6 (Scheme 3). In the presence of the Lewis acid, filtration, and no further purification was needed. The fi-
the hexahydrotriazine might be in equilibrium with a bo- nal removal of the phthalimide group with methylamine in
ron trifluoride complex of the unstable monomeric form- ethanol14 gave compound 8 as a racemic mixture (Scheme
aldimine, which then reacts with the ketene in the 4).
presence of Et3N to give C-4 unsubstituted azetidin-2-
ones 4a-f (Scheme 3).
Scheme 4
The racemate was separated by enzymatic kinetic resolu-
tion using Penicillin G Acylase (PGA).15 PGA is an en-
zyme produced by E. Coli that is capable of transferring a
Scheme 3
phenylacetyl group from esters, amides or acids to accep-
tor molecules such as alcohols, amines or water. It is used
on an industrial scale for the production of 6-APA-, in
peptide protective group chemistry and for the resolution
of alcohols.16 To be suitable for enzymatic hydrolysis,
(R,S)-8 was first converted to the racemic phenylacetami-
do derivative (R,S)-9 by treatment with phenylacetylchlo-
ride under Schotten−Baumann conditions. The enzymatic
kinetic enantioselective hydrolysis of (R,S)-9 led to the S-
enantiomer of 8, while the R-enantiomer remained as such
and the two species could be separated through a simple
acid-base extraction (Scheme 5).
The choice of the protecting groups for the two nitrogen
atoms was critical for the synthesis. Two kinds of protect-
ing groups were tested for the amino group at C-3, while
three were tested for N-1. In each case, the b-lactams
were formed in good yields (Table).12 The reactions were
performed in dichloromethane at -40 °C by treating one
equimolar amount of acid chloride with excess triethyl-
amine, and then adding to a solution of the resulting
unstable ketene a dichloromethane solution of hexa-
hydrotriazine and BF3•OEt2 at the same temperature.
A simple trituration in CH3OH was needed to obtain
b-lactams 4a-c.
For the reminder of the synthesis, the best results were ob-
tained using phthalimidoacetyl chloride and N,N′,N′′-tri-
allylhexahydrotriazine (b-lactam 4a). In all other cases,
the protecting groups presented several compatibility
problems with the other b-lactam functions in the depro-
tection phase. Compound 4a was then converted to the
corresponding propen-1-yl derivative 7 in good overall
yield by isomerization of the N-allylic sidechain. This
passage, which is the first step in the oxidative chain
Table Synthesis of Azetidinones 4a-f
Scheme 5
Entry R1, R2
R
Product Yield (%)a
1
2
3
4
5
6
R1, R2 = Pht
CH2CH=CH2
p-OMePh
CH2Ph
4a
4b
4c
4d
4e
4f
75
80
68
80
63
57
The hydrolysis was carried out by incubating (R,S)-9 in
phosphate buffer (pH 7.8) and acetone as a cosolvent at
r.t. with PGA immobilized on Eupergit C beads (10% w/
w). These conditions were established through a detailed
study17 of the resolution of (R,S)-9 performed by monitor-
ing the course of the e.e.% in relation to the conversion at
various pH values, temperatures and amount of enzyme.
Since the pH of the reaction decreases during the hydrol-
ysis, the rates of the reaction and conversion were moni-
tored by the amount of 0.1N NaOH added to maintain the
“
“
R1=R2=Cbz
CH2CH=CH2
p-OMePh
CH2Ph
“
“
aIsolated yields.
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A Total Synthesis of (1R,5R)-3-phenylmethyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-one
291
initial value. At the desired conversion, the crude reaction
mixture was extracted at pH 4.5 with ethyl acetate, and the
(S)-3-amino-azetidin-2-one (S)-8 was separated in the
aqueous phase and directly rederivatized to (S)-3-phenyl-
acetamido-azetidin-2-one (S)-9. The presence of the N-1
propenylic chain is important, in fact, a completely depro-
tected b-lactam would have been too hydrophilic and the
extraction in the organic phase would have been more dif-
ficult.
During the initial stage of the reaction, enantiomerically
pure (S)-8 was found to be the product of the hydrolysis
and a good kinetic resolution was achieved for conver-
sions of 30% (e.e. > 94%) and 40% (e.e. >86%). At 60%
conversion, the remaining substrate fraction (R)-9 result-
ed in e.e. = 89%, so that both enantiomers could be ob-
tained with a good degree of purity depending on the rate
of conversion.
Scheme 6
from which traces of the 3-acetoxy derivative could be re-
covered.
These difficulties could be overcome by oxidizing an aze-
tidinone derivative with an N-1-unsubstituted β-lactam
ring and double-protected C-3 nitrogen. For this purpose,
(S)-9 was converted to (S)-11 with sodium hydride and
carbobenzoxy chloride in THF at room temperature. The
resulting b-lactam was then deprotected by oxidation with
potassium permanganate to afford 12 (Scheme 7).
Figure Dependence of ee% of (S)-9 (♦ ) and of (R)-9 ( ) on the %
conversion during enzymatic resolution. Experimental conditions:
phosphate buffer/acetone 2:1; 25°C; pH 7.8; PGA (10% w/w).
Scheme 7
The enantiomer (S)-9 was used for the following synthe-
sis; the enantiomer(R)-9 can be used in the same way and
with an identical procedure to obtain specular thiazoline
and enantiomers of b-lactam antibiotics.
Oxidation of 12 with the Murahashi procedure finally led
to 13 in good overall yield and with complete diastereose-
lective induction. The final step in the synthesis involved
removal of the carbobenzoxy group by hydrogenolysis
under mild conditions in THF using Pd on activated char-
coal as a catalyst to give 3 (Scheme 8).20
To increase the yield of resolution from 40% to complete-
ness, product (R)-9 was racemized through a simple pro-
cedure and recycled, as shown in Scheme 6. To achieve
racemization, the (R) enantiomer of b-lactam 9 was hy-
drolyzed with PGA to give (R)-8 and then reacted with
benzaldehyde to furnish the corresponding phenyl imine
10. This compound is quite acidic at the C-3 position and
treatment with a catalytic amount of t-BuOK was suffi-
cient to establish an equilibrium with the planar 1,3 aza-
allylanion. After refunctionalization, racemic 9 (R,S) is
obtained and the product can be submitted again to the en-
zymatic resolution.
Scheme 8
The 4-acetoxy group was introduced by ruthenium-cata-
lyzed oxidation with peracetic acid following the Mura-
hashi procedure.18 However, preliminary experiments19
showed that the oxidation failed when the β-lactam nitro-
gen was protected; for example, the reaction did not take
place when it was carried out on N-1-substituted com-
pounds such as 7. Moreover, the substituent on the C-3
amino group played an important role: when a mono-sub-
stituted amide was tested, we observed a complex mixture
Compound 3 was then converted into the corresponding
thioamide by means of phosphorus pentachloride and
treatment of the resulting chloroimine with hydrogen sul-
fide. Formation of the unstable chloroimine is industrially
exploited to deprotect a phenylacetamide chain by
quenching with excess alcohol,21 whereas in this case
quenching with H2S furnished compound 2, the yield of
which is not yet optimized. Upon treatment with TEA,
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G. Cainelli et al.
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4c: mp 119 °C.
IR (nujol): 1760, 1720 cm-1.
1H NMR (200 MHz, CDCl3): d = 3.53 (dd, 1H, J = 5.4, 5.4 Hz), 3.58
(dd, 1H, J = 5.4, 3.2 Hz), 4.45 (d, 1H, J = 15.3 Hz), 4.68 (d, 1H,
J = 15.3 Hz), 5.48 (dd, 1H, J = 5.4, 3.2 Hz), 7.3 (m, 5H), 7.8 (m,
4H).
(3S)-phenylthioacetamido-(4S)-acetoxyazetidin-2-one 2
easily and quantitatively underwent cyclization to give the
target compound 1.
13C NMR (50 MHz, CDCl3): d = 166.8, 164.7, 134.6, 134,4, 134.3,
133.9, 131.5, 128.7, 128.6, 128.5, 123.8, 123.5, 53.5, 46.1, 45.4.
HRMS: m/z calc for C18H14N2O3 (M+) 306.1004. Found: 306.1001.
Azetidinones 4d-f; General Procedure
Scheme 9
To a solution of N,N-dicarbobenzyloxyglycine (343 mg, 1 mmol) in
CH2Cl2 (10 mL) at r.t., oxalyl chloride (1.5 mmol, 0.13 mL) was
added to form the corresponding acyl chloride. After the mixture
was stirred for 3 h, the temperature was brought to -40 °C and the
same procedure for b-lactams 4a-c was used. The products were pu-
rified by chromatography over silica gel (cyclohexane/ EtOAc 8:2).
In conclusion, we realized a total synthesis of homochiral
thiazoline 1, a useful intermediate for the synthesis of pen-
icillin and cephalosporin derivatives. This synthesis in-
volves facile processes using inexpensive and readily
available starting materials, while chirality is introduced
through enzymatic resolution followed by recycling of the
undesired enantiomer.
4d: mp 75 °C.
IR (CHCl3): 1760, 1700 cm-1.
1H NMR (200 MHz, CDCl3): d = 3.34 (dd, 1H, J = 5.1, 2.9 Hz), 3.44
(dd, 1,H, J = 5.2, 5.1 Hz), 3.54 (dd, 1H, J = 5.2, 15.6 Hz), 3.76 (dd,
1H, J = 5.2, 15.6 Hz), 5.11−5.27 (m, 6H), 5.48−5.68 (m, 2H), 7.35
(m, 10H).
Penicillin G Amidase (PGA), used for the enzymatic resolution,
was kindly supplied by Recordati (Italy). The enantiomeric excess
was determined by HPLC: HP1900, direct phase, chiral column S,S-
DACH.DNB Lichosorb si.100, 5 micron 25cm x 4mm, kindly pro-
vided by Prof. Gasparrini, University of Rome (Italy). Hexahydro-
triazines 6 were prepared following the procedure reported in the
literature9 using EtOAc as a solvent instead of benzene.
13C NMR (50 MHz, CDCl3): d = 165.8, 152.5, 134.5, 131.3, 128.6,
128.5, 128.4, 118.6, 69.5, 59.8, 45.9, 44.3.
HRMS: m/z calc for C22H22N2O5 (M+) 394.1529). Found: 394.1527.
4e: mp 73 °C.
IR (CHCl3): 1744, 1703 cm-1.
1H NMR (200 MHz, CDCl3): d = 3.65 (dd, 1H, J = 5.4, 3.1 Hz), 3.81
(s, 3H), 3.82 (dd, 1H, J = 5.4, 5.5 Hz), 5.24 (m, 4H), 5.69 (dd, 1H,
J = 5.5, 3.1 Hz), 6.84 (m, 2H), 7.18 (m, 2H), 7.27 (m, 10H).
Azetidinones 4 a-c; General Procedure
To a solution of phthalimidoacetyl chloride (30 mmol, 6.7 g) cooled
at -40 °C in anhyd CH2Cl2 (80 mL), Et3N (60 mmol, 8.4 mL) was
added dropwise. The solution became yellow and then orange to
confirm that the ketene was formed. After 30 min at -40 °C, a solu-
tion of the appropriate hexahydrotriazine 6 (10 mmol) and
BF3•OEt2 (30 mmol, 3.68 mL) in CH2Cl2 (80 mL), previously
mixed at r.t., was added dropwise. After 4 h at -40 °C, the solution
was quenched with HCl (1 M, 40 mL) and extracted with CH2Cl2
(2 x 30 mL). The organic phase was washed with aq NaHCO3 (5%,
40 mL), brine (40 mL), dried (Na2SO4) and concentrated in vacuo.
The products 4a-c were obtained as white solids after careful tritu-
ration in CH3OH.
13C NMR (75.5 MHz, CDCl3): d = 162.0, 156.1, 152.3, 134.2,
131.5, 128.5, 128.4, 117.7, 114.3, 69.6, 59.2, 55.5, 45.7.
HRMS: m/z calc for C26H24N2O6 (M+) 460.1634. Found: 460.1637.
4f: IR (CHCl3): 1759, 1700 cm-1.
1H NMR (300 MHz, CDCl3): d = 3.29 (dd, 1H, J = 5.1, 3.0 Hz), 3.35
(dd, 1H, J = 5.4, 5.1 Hz), 4.02 (d, 1H, J = 15.0 Hz), 4.44 (d, 1H,
J = 15.0 Hz), 5.1 (m, 4H), 5.55 (dd, 1H, J = 5.4, 3.0 Hz), 7.2−7.4
(m, 15H).
13C NMR (75.5 MHz, CDCl3): d = 165.7, 152.4, 135.0, 134.5,
128.6, 128.5, 128.4, 128.2, 128.1, 127.9, 69.4, 59.9, 45.8, 45.7.
HRMS: m/z calc for C26H24N2O5 (M+) 444.1685. Found: 444.1683.
4a: mp 87 °C.
IR (nujol): 1759, 1717 cm-1.
1H NMR (200 MHz, CDCl3): d = 3.63 (dd, 1H, J = 5.4, 5.4 Hz), 3.70
(dd, 1H, J = 5.4, 2.9 Hz), 3.85 (dd, 1H, J = 5.5, 15.7 Hz), 4.10 (dd,
1H, J = 5.5, 15.7 Hz), 5.25−5.42 (m, 2H), 5.45 (dd, 1H, J = 2.9, 5.4
Hz), 5.90 (m, 1H), 7.80 (m, 4H).
13C NMR (75.5 MHz, CDCl3): d = 167.0, 164.7, 134.4, 131.7,
131.1, 123.6, 118.8, 53.6, 45.5, 44.7.
3-N-(Phthalimido)-1-N-(propen-1-yl)azetidin-2-one (7)
Azetidin-2-one 4a (10.24 g, 40 mmol) was suspended in 90 mL of
EtOH and 10 mL of H2O; 150 mg of RhCl3.nH2O were added and
the solution was heated to reflux. After consumption of the starting
material (30 min), the solution was poured into cold water (40 mL)
causing product precipitation. After separation by filtration, to elim-
inate the dark color, the b-lactam was dissolved in CH2Cl2 and treat-
ed with carbon, filtered, dried and concentrated, to give 7 in 98%
yield. mp 173 °C.
HRMS: m/z calc for C14H12N2O3 (M+) 256.0848. Found: 256.0849.
4b: mp 192 °C.
IR (nujol): 1750, 1710 cm-1.
IR (nujol): 1775, 1745, 1720 cm-1.
1H NMR (300 MHz, CDCl3): d = 3.80 (s, 3H), 4.00 (m, 2H), 5.56
(dd, 1H, J = 5.4, 3.4 Hz), 6.90−7.35 (m, 4H), 7.75−7.85 (m, 4H).
13C NMR (75.5 MHz, CDCl3): d = 166.9, 160.9, 156.4, 134.5,
131.6, 131.3, 123.7, 118.0, 114.4, 55.5, 52.8, 45.3.
1H NMR (300 MHz, CDCl3): d = 1.74 (dd, 3H, J = 7.1, 1.6 Hz), 3.82
(m, 2H), 5.17 (dq, 1H, J = 7.1, 14.2 Hz), 5.5 (dd, 1H, J = 3.2, 5.5
Hz), 6.66 (dd, 1H, J = 1.6, 14.2 Hz), 7.8 (m, 4H).
13C NMR (75.5 MHz, CDCl3): d = 166.7, 160.5, 134.3, 131.5,
123.5, 121.9, 108.5, 52.7, 45.1, 14.6.
HRMS: m/z calc for C18H14N2O4 (M+) 322.0954. Found: 322.0950.
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A Total Synthesis of (1R,5R)-3-phenylmethyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-one
293
HRMS: m/z calc for C14H12N2O3 (M+) 256.0848. Found: 256.0850.
1H), 5.15 (dq, 1H, J = 6.8, 14.2 Hz), 6.59 (dd, 1H, J = 1.5, 14.2 Hz),
7.2−7.8 (m, 5H), 8.48 (s, 1H).
13C NMR (50 MHz, CDCl3): d = 164.2, 164.0, 135.5, 131.3, 128.6,
3-Amino-1-N-(propen-1-yl)azetidin-2-one (8)
To a suspension of 7 (10 mmol, 2.56 g) in EtOH (15 mL), was added
MeNH2 (10 mL, 33% in EtOH, 8.32 M). The solution became clear
but, after 3h at r.t., the phthalimido derivative began to precipitate
whereas, product 8 remained in solution and was recovered after fil-
tration in 80% yield.
128.4, 122.2, 108.2, 72.7, 47.4, 14.7.
HRMS: m/z calc for C13H14N2O (M+) 214.1106. Found: 214.1105.
Regeneration of (R,S)-9
Imine (R)-10 was dissolved in THF (5 mL) and treated at 0 °C with
a catalytic amount of t-BuOK (0.1 mL, 1M solution in THF). After
3 h at r.t., HCl (1N, 0.5 mL) was added. After 1 h, Na2CO3 (216 mg,
2 mmol) and phenylacetylchloride (0.16 mL, 1.2 mmol) were added
IR (CHCl3): 3300, 1750 cm-1.
1H NMR (200 MHz, CDCl3): d = 1.67 (dd, 3H, J = 1.6, 6.8 Hz),
2.53 (br s, 2H), 3.11 (dd, 1H, J = 6.4, 2.6 Hz), 3.64 (dd, 1H, J = 5.9,
6.3 Hz), 4.20 (dd, 1H, J = 2.6, 5.9 Hz), 5.1 (dq, 1H, J = 14.8, 6.8
Hz), 6.5 (dd, 1H, J = 14.8, 1.6 Hz).
to the mixture to give (R,S)-9 in 90% yields. [a]25 0 (c = 4,
D
CH2Cl2); e.e.% = 0 confirmed by HPLC (chiral column).
13C NMR (75.5 MHz, CDCl3): d = 162.0, 122.2, 122.1, 107.6, 65.3,
(3S)-3-N-(Benzyloxycarbonyl)-3-N-(phenylacetyloxy)-1-N-
(propen-1-yl)aminoazetidin-2-one (11)
47.9, 24.3.
HRMS: m/z calc for C6H10N2O (M+) 126.0793. Found: 126.0790.
b-lactam (S)-9 (256 mg, 1 mmol) was slowly dropped into a suspen-
sion of NaH (42 mg, 1.9 mmol) in THF (5 mL) at 0 °C. After 10
min, benzyl chloroformate (0.27 mL, 1.9 mmol) was added. After
20 min at r.t., the reaction was quenched with NH4Cl, extracted with
EtOAc, washed with brine, dried and concentrated. After purifica-
tion by flash chromatography (cyclohexane/EtOAc 8:2), the prod-
uct was obtained in 65% yield; mp: 85 °C; [a]25D -56.6 (c = 0.514,
CHCl3).
3-N-(Phenylacetyloxy)-1-N-(propen-1-yl)aminoazetidin-2-one
(9)
To a solution of 8 (1.26 g, 10 mmol) and Na2CO3 (20 mmol) in ac-
etone (15 mL) and H2O (20 mL), at 0 °C, phenylacetyl chloride (12
mmol, 1.59 mL) was added dropwise. After 12 h at r.t., acetone was
concentrated and the mixture was extracted with EtOAc (2 ¥ 20
mL). The organic phase was washed with brine, dried and concen-
trated to directly obtain the product as a white solid in 85% yield;
mp 102 °C.
IR (CHCl3): 1760, 1700 cm-1.
1H NMR (200 MHz, CDCl3): d = 1.61 (dd, 3H, J = 6.8, 1.6 Hz), 3.36
(dd, 1H, J = 3.2, 5.6 Hz), 3.57 (dd, 1H, J = 5.8, 5.6 Hz), 4.26 (s,
2H), 4.86 (dq, 1H, J = 7.0, 14.2 Hz), 5.16 (d, 1H, J = 11.0 Hz), 5.28
(d, 1H, J = 11.0 Hz), 5.75 (dd, 1H, J = 3.2, 5.8 Hz), 6.36 (dd, 1H,
J = 1.6, 14.2 Hz), 7.2−7.4 (m, 10H).
13C NMR (50 MHz, CDCl3): d = 173.5, 162.1, 152.9, 133.8, 133.7,
129.5, 129.4, 129.3, 129.0, 128.9, 128.7, 127.0, 133.8, 133.7, 121.9,
107.2, 69.7, 57.2, 45.2, 44.3, 14.6.
IR (CHCl3): 3300, 1752, 1655 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.68 (d, 3H, J = 6.6 Hz), 3.25 (dd,
1H, J = 2.6, 6.1 Hz), 3.56 (s, 2H), 3.65 (dd, 1H, J = 6.1, 6.5 Hz), 4.9
(m, 1H), 5.06 (dq, 1H, J = 14.2, 6.9 Hz), 6.42 (d, 1H, J = 14.2), 7.08
(d, 1H, J = 7.41 Hz), 7.2−7.4 (m, 5H).
13C NMR (75.5 MHz, CDCl3): d = 171.5, 162.8, 134.3, 129.2,
128.8, 128.7, 127.7, 127.1, 121.8, 108.5, 55.2, 47.4, 43.0, 14.6.
HRMS: m/z calc for C22H22N2O4 (M+) 378.1579. Found: 378.1577.
HRMS: m/z calc for C14H16N2O2 (M+) 244.1212. Found: 244.1213.
(3S)-3-N-(Benzyloxycarbonyl)-3-N-(phenylacetyloxy)
aminoazetidin-2-one (12)
Enzymatic Hydrolysis
Compound 9 (100 mg, 0.41 mmol) was dissolved in acetone (2 mL)
and diluted with 0.1 M phosphate buffer (4 mL) at pH 7.8. The en-
zyme (40 IU, 10% w/w) was added and the mixture stirred at 1000
rpm. The pH was maintained to its initial value with the automatic
addition of NaOH (0.1N). At the desired conversion (30%), the sup-
ported enzyme was filtered off, acetone was eliminated in vacuo,
the pH of the aq phase was adjusted to 4.5 with dilute HCl and ex-
tracted with EtOAc (3 ¥ 10 mL). The organic phase (R)-9 was col-
lected. The aq phase containing (S)-8 was treated with Na2CO3 (to
pH 8) and phenylacetyl chloride (1.5 equiv) in acetone (10 mL) to
obtain, after removal of acetone in vacuo and extraction with EtOAc
To a solution of 13 (10 mmol, 3.78 g) in acetone (40 mL) and phos-
phate buffer (20 mL, pH 7.5), KMnO4 (12 mmol, 1.740 g) dissolved
in 5 mL of buffer was slowly added dropwise at a rate such that the
-
passage from purple (MnO4 ) to brown (MnO2) was observed. This
change indicated that the oxidation was going on. After consump-
tion of the last drop, MnO2 was filtered off, the solution was con-
centrated to eliminate acetone, extracted with CH2Cl2, washed with
brine, dried and concentrated. The product was obtained in 59%
yield after purification by flash chromatography (cyclohexane/
EtOAc 1:1), [a]25D -32.2 (c = 4.12, CHCl3).
IR (neat): 3300, 1760, 1748, 1670 cm-1.
(3 ¥ 10 mL), compound (S)-9: [a]25 -30 (c = 0.9, CHCl3);
e.e. = 94% (HPLC).
D
1H NMR (200 MHz, CDCl3): d = 3.40 (dd, 1H, J = 3.2, 5.4 Hz), 3.48
(dd, 1H, J = 5.4, 5.5 Hz), 4.24 (s, 2H), 5.20 (d, 1H, J = 11.7 Hz),
5.29 (d, 1H, J = 11.7 Hz), 5.69 (dd, 1H, J = 3.2, 5.5 Hz), 5.84 (br s,
1H), 7.21−7.38 (m, 10H).
13C NMR (75.5 MHz, CDCl3): d = 173.6, 167.4, 153.0, 134.1,
133.9, 129.9, 129.1, 129.0, 128.9, 128.8, 128.7, 127.0, 69.6, 59.8,
44.4, 42.2.
Racemization Process
b-Lactam (R)-9 was completely transformed into (R)-8 by means of
PGA in the same conditions of enzymatic hydrolysis with longer re-
action times. After recovering by extraction with CH2Cl2 at pH 8,
(R)-8 (126 mg, 1 mmol) was dissolved in CH2Cl2 (5 mL) at r.t. and
treated with benzaldehyde (0.1 mL, 1 mmol) and MgSO4 (2 mmol)
to give quantitatively imine (R)-10. The product was recovered by
filtration and the solvent evaporated.
[a]25D +162 (c = 1.1, CH2Cl2).
IR (CHCl3): 1769, 1638 cm-1.
1H NMR (200 MHz, CDCl3): d = 1.72 (dd, 3H, J = 6.8, 1.5 Hz), 3.63
(dd, 1H, J = 2.3, 6.1 Hz), 3.82 (dd, 1,H, J = 6.1, 5.1 Hz), 4.88 (m,
HRMS: m/z calc for C19H18N2O4 (M+) 338.1266. Found: 338.1268.
(3S,4R)-3-N-(Benzyloxycarbonyl)-3-N-(phenylacetyloxy)
amino-4-acetoxyazetidin-2-one (13)
A mixture of Ru (5%) on carbon (80 mg, 0.04 mmol), anhyd sodium
acetate (82 mg, 1 mmol), HOAc (1 mL), b-lactam 12 (1 mmol) and
CH2Cl2 (3 mL) was charged into a 25 mL flask at r.t. To the above
mixture, a 32% solution of AcOOH in HOAc (0.46 mL, 2.2 mmol)
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G. Cainelli et al.
PAPER
was added dropwise over a period of 1 h at r.t., and stirred for 2 h.
The mixture was poured into cold water, filtered and extracted with
CH2Cl2 (3 ¥ 15 mL). The organic solution was washed with 10%
Na2SO3 (20 mL), brine and dried (Na2SO4). Evaporation, followed
by column chromatography on silica gel (cyclohexane/EtOAc 6:4)
gave 13 in 63% yield as a single trans diastereoisomer, [a]25D -33.9
(c = 1.65, CHCl3).
References
(1) Niccolai, D.; Tarsi, L.; Thomas, R. J. J. Chem. Soc., Chem.
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Berks, A. H. Tetrahedron 1996, 52, 331.
The Organic Chemistry of b-Lactams; Georg, G. I., Ed.; VCH:
New York, 1993.
(2) Bucourt, R. In Recent Advances in the Chemistry of b-Lactam
Antibiotics; Gregory G. I. Ed., Second International
Symposium; London, 1980; and references cited therein.
(3) Cooper, R. D. G. J. Am. Chem. Soc. 1970, 92, 2575.
Brain, E. G.; Eglinton, A. J.; Nayler, J. H. C.; Pearson, M. J.;
Southgate, R. J. Chem. Soc., Perkin I trans. 1976, 447.
(4) Cooper, R. D. G.; José, L. F. J. Am. Chem. Soc. 1972, 94,
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Arcamone, F. J. Chem. Soc., Chem. Comm. 1978, 1101.
Marchand-Brynaert, J.; Ghosez, L. Tetrahedron Lett. 1980,
21, 3085.
IR (CHCl3): 3300, 1800, 1750, 1700, 1257 cm-1.
1H NMR (300 MHz, CDCl3): d = 2.06 (s, 3H), 4.26 (m, 2H), 5.25
(s, 2H), 5.6 (d, 1H, J = 0.8 Hz), 5.9 (d, 1H, J = 0.8 Hz), 6.42 (br s,
1H); 7.2−7.5 (m, 10H).).
13C NMR (75.5 MHz, CDCl3): d = 173.8, 170.0, 163.3, 152.5,
133.6, 129.5, 129.3, 129.0, 128.8, 128.7, 128.5, 127.2, 78.0, 69.9,
65.6, 44.3, 20.6.
HRMS: m/z calc for C21H20N2O6 (M+) 396.1321. Found: 396.1320.
(3S, 4R)-3-N-(Phenylacetyloxy)amino-4-acetoxyazetidin-2-one
(3)
To a solution of 13 (396 mg, 1 mmol) in THF (10 mL), Pd (10%) on
activated charcoal (20 mg) were added. The reaction funnel was
connected with a plastic balloon containing H2 at the pressure of 1
atm and the reaction was monitored by TLC. After total consump-
tion of the starting material (30−60 min), the Pd was filtered off and
Ghosez, L.; Marchand-Brynaert, J.; Vekemans, J.; Bodgan, S.
Tetrahedron 1983, 39, 2493.
(6) Narisada, M.; Onoue, H.; Ohtani, M.; Watanabe, F.; Okada,
T.; Nagata, W. Tetrahedron Lett. 1978, 20, 1755.
(7) Osborne, N. F. J. Chem. Soc., Perkin Trans. I 1982, 1435.
(8) Cainelli, G.; Panunzio, M.; Giacomini, D.; Martelli, G.;
Spunta, G.; Bandini, E. In Chemical Synthesis: Gnosis to
Prognosis; Chatgilialoglu, C; Snieckus,V. Eds.; NATO ASI,
1996.
(9) Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta,
G. Tetrahedron 1996, 52, 1685.
(10) Kamiya, T.; Hashimoto, M.; Nakaguchi, O.; Oku, T.
Tetrahedron 1979, 35, 323.
(11) Reynolds, D.; Cossar, B. J. Heterocycl. Chem. 1971, 8, 567.
(12) Cainelli, G.; Giacomini, D.; Galletti P. Synlett 1998, 6, 611.
(13) Georg, G. I.; He, P.;Kant, J.; Mudd, J. Tetrahedron Lett. 1990,
31, 451.
(14) Motawia, H. S.; Wengel, J.; Abdel-Megid, A. E. S., Pedersen,
E. B. Synthesis 1989, 384.
the THF was concentrated in vacuo affording 3 in 98% yield, [a]25
D
-50 (c = 0.4, CHCl3).
IR (CHCl3): 1793, 1750, 1680 cm-1.
1H NMR (300 MHz, CDCl3): d = 2.14 (s, 3H), 3.65 (s, 2H), 4.65 (d,
1H, J = 6.4 Hz), 5.84 (s, 1H), 6.13 (d, 1H, J = 6.4 Hz), 6.77 (br s,
1H), 7.27 (m, 5H).
13C NMR (75.5 MHz, CDCl3): d = 171.7, 170.8, 164.1, 133.8,
129.5, 129.2, 127.7, 78.6, 63.9, 43.2, 20.7.
HRMS: m/z calc for C13H14N2O4 (M+) 262.0953. Found: 262.0955.
(1R, 5R)-3-Phenylmethyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-
en-7-one (1)
To a solution of 3 (262 mg, 1 mmol) in CH2Cl2 (10 mL) at r.t., t-
BuMe2SiCl (225mg, 1.5 mmol) and 4-dimethylaminopyridine (245
mg, 2 mmol) were added. After 12h, the temperature was brought
to -50 °C, dimethylaniline (0.313 mL, 2.5 mmol) and PCl5 (230 mg,
1.1 mmol) were added and, after 3h at low temperature, H2S was
bubbled inside the reaction funnel for 30 min. The mixture was al-
lowed to reach r.t., quenched with NaHCO3 (10%, 20 mL), extract-
ed with CH2Cl2 (2 ¥ 20 mL), washed with brine, dried and
concentrated. The intermediate thioamide 2 thus obtained was di-
rectly converted into 1 by refluxing for 1h in toluene (10 mL) in the
presence of Et3N (0.125 mL, 1 mmol) and then stirring overnight at
r.t. After quenching with H2O (5 mL) and extraction with EtOAc
(2 ¥ 10 mL), the product was obtained in 98% yield after purifica-
tion with flash chromatography (cyclohexane/EtOAc 1:1); mp
178 °C, [a]25D +91.8 (c = 1.23, CHCl3).
(15) Duggleby, H. J.; Tolley, S. P.; Hill, C. P.; Dodson, E. J.;
Dodson, G.; Moody, P. C. E. Nature 1995, 373, 264.
(16) See for example: Baldaro, E.; Fuganti, C.; Servi, S.; Tagliani,
A.; Terreni, M. In Microbial Reagents in Organic Synthesis;
Kluwer Academic: 1992; p 175.
(17) Cainelli, G.; Giacomini, D.; Galletti P.; DaCol, M.
Tetrahedron Asymmetry 1997, 8, 3231.
(18) Murahashi, S-I; Saito, T.; Naota, T.; Kumobayashi, H.;
Akutagawa, S. Tetrahedron Lett. 1991, 32, 2145.
Murahashi, S-I; Naota, T.; Kuwabara, T.; Saito, T.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1990,
112, 7820.
(19) Cainelli, G.; DaCol, M.; Galletti P.; Giacomini, D. Synlett
1997, 8, 923.
(20) Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Chemistry; J. Wiley Eds., New York, 1991.
(21) Hatfield, L. D.; Lunn, W. H.; Jackson, B. G.; Peters, L. R.;
BlaszczaK, L. C.; Fisher, J. W.; Gardner, J. P.; Dunigan, J. M.
In Recent Advances in the Chemistry of b-Lactams
Antibiotics; Second International Symposium, Gregory, G. I.
Ed., R. S. C.: London, 1980.
IR (CHCl3): 3200, 1741, 1720, 1710 cm-1.
1H NMR (300 MHz, CDCl3): d = 3.87 (d, 1H, J = 15.3 Hz), 4.0 (d,
1H, J = 15.3 Hz), 5.50 (d, 1H, J = 3.9 Hz), 6.01 (m, 1H), 6.58 (br s,
1H), 7.26−7.36 (m, 5H).
13C NMR (75.5 MHz, CDCl3): d = 172.5, 164.8, 135.0, 129.1,
128.7, 127.4, 94.8, 64.3, 41.5.
HRMS: m/z calc for C11H10N2OS (M+) 218.0514. Found: 218.0514.
Article Identifier:
1437-210X,E;2000,0,02,0289,0294,ftx,en;Z05999SS.pdf
Acknowledgement
This work was financially supported by MURST (40 and 60%),
CNR, University of Bologna (fund for selected topics).
Synthesis 2000, No. 2, 289–294 ISSN 0039-7881 © Thieme Stuttgart · New York