N,N-dibenzyloxycarbonylglycyl chloride as useful ketene equivalent in the synthesis of azetidin-2-ones

Article abstract of DOI:10.1055/s-1998-1726

N,N-3-Dibenzyloxycarbonylaminoazetidin-2-ones have been conveniently prepared from N,N-dibenzyloxycarbonylglycyl chloride and imines or hexahydrotriazines. The β-lactams thus obtained could be monodeprotected by mild hydrogenolysis with Pd on carbon.

Full text of DOI:10.1055/s-1998-1726

June 1998
SYNLETT
611
N,N-Dibenzyloxycarbonylglycyl Chloride as Useful Ketene Equivalent in the Synthesis of
Azetidin-2-ones
Gianfranco Cainelli,* Paola Galletti, Daria Giacomini*
Dipartimento di Chimica “G.Ciamician”, Via Selmi, 2, I-40126 Bologna (Italy)
Telefax: Int. code + (51)25-9456; e-mail: cainelli@ciam.unibo.it
Received 12 March 1998
Abstract: N,N-3-Dibenzyloxycarbonylaminoazetidin-2-ones have been
conveniently prepared from N,N-dibenzyloxycarbonylglycyl chloride
and imines or hexahydrotriazines. The β-lactams thus obtained could be
monodeprotected by mild hydrogenolysis with Pd on carbon.
Penicillins, cephalosporins and other major β-lactam antibiotics are
characterized by the presence of a 3-aminoazetidin-2-one unit. Their
Scheme 2
1
synthesis was performed either via Staudinger reaction or via the ester-
2
enolate imine route. In the former, in order to have a nitrogen bonded to
formaldehyde imines for the preparation of monocyclic 4-unsubstituted
β-lactams.
the C-3 position, azidoacetyl chloride (Bose reaction) or
phthalimidoacetyl chloride were the most utilized reagents, while in the
latter the enolate of 1-(ethoxycarbonylmethyl)-2,2,5,5-tetramethyl-1-
aza-2,5-disilacyclopentane (STABASE) was largely employed.
10
Recently, we reported a synthesis of the 3-amino-4-acetoxyazetidin-2-
3
one through a C-4 oxidation by ruthenium catalysts. We emphasized
the urgency to have a C-3 full protected nitrogen atom in order for the
C-4 oxidation to be successful. In this perspective, the phthalimido
4
group works well, but suffers by the need of a difficult cleavage. The
yield of this hydrolysis depends strongly on the substrate and, in
general, the conditions required are too drastic for azetidinones.
In connection with our ongoing interest in exploring new synthetic
routes for β-lactams, we now report an easy and convenient method,
starting from N,N-dibenzyloxycarbonylglycyl chloride, to prepare N,N-
3-dibenzyloxycarbonylaminoazetidin-2-ones and deprotect them under
mild conditions to the N-benzyloxycarbonylamino derivatives.
Scheme 3
When the N,N-dibenzyloxycarbonylglycyl chloride 3 was treated with
imines, C substituted azetidinones 7-10 were obtained (Scheme 3). The
4
simple diastereoselectivity plays in favor of the cis isomer. The relative
1
cis/trans stereochemistry was unequivocally determined by H NMR
spectroscopy on the basis of the coupling constants (cis: J = 5.7-5.9
3,4
Hz and trans: J = 2.5-3.0 Hz). It is noteworthy that we preferentially
3,4
obtained cis azetidinones also with N-phenylbenzaldimine while it is
known that the reaction of phthalimidoacetyl chloride with the same
11
imine gives the corresponding trans β-lactam. The N-benzylimine of
12
(2S)-lactal 9 furnished, in this approach, the optically active cis
Scheme 1
20
azetidinone 7 as a single isomer ([α]
= +16.7, c = 0.936, CHCl ). The
3
D
stereochemistry of this product was determined by analogy with known
compounds. The total cis-syn asymmetric induction observed in this
13
The N,N-dibenzyloxycarbonylglycine 2 was obtained in a 60% overall
yield through alkylation of potassium dibenzyl iminodicarboxylate with
case, is particularly noteworthy when compared with the trans-syn one
obtained with the STABASE enolate imine cycloaddition. This
stereochemical result implies that the natural (S)-C3 configuration could
be obtained starting from the easily available (2S)-lactal.
5
13
tert-butyl bromoacetate to give 1 and subsequent deprotection of tert-
6
butyl group with TiCl (1.5 eq., CH Cl , 0°C, 1 min). The new ketene
4
2
2
equivalent 3 was formed in situ by adding oxalyl chloride to the
corresponding glycine derivative 2 (1.5 eq., CH Cl , rt, 3h) (Scheme 1).
2
2
Exposure of β-lactams 4, 7, 10 to H (1 atm) in THF at room
2
N,N-Dibenzyloxycarbonylglycyl chloride 3 in the presence of NEt
3
temperature in the presence of a catalytic amount of Pd (10% on C for
short reaction time or Lindlar catalyst) provided the corresponding
monobenzyloxycarbonylamino derivatives in almost quantitative yields
7
reacts with imines or hexahydrotriazines affording β-lactams 4-8 and
8
10 in satisfactory yields.
14
(Scheme 4).
N-Allyl, N-benzyl, and N-p-methoxyphenylhexahydrotriazines were
previously treated with BF •OEt in CH Cl according to a modified
In conclusion, we have demonstrated that the N,N-
3
2
2
2
9
Kamiya procedure and then added at -40 °C to a dichloromethane
dibenzyloxycarbonylglycyl chloride constitutes
a useful ketene
solution of 3 and Et N to afford β-lactams 4-6 (Scheme 2). In this
equivalent for the synthesis of C4-unsubstituted 3-aminoazetidin-2-ones
3
approach, hexahydrotriazines served as a useful equivalent of the elusive
and cis C-4 substituted as well. The selective hydrogenolysis to mono

612
LETTERS
SYNLETT
aqueous washes were re-extracted with CH Cl (2 x 20 mL) and
2
2
the combined organic layers were dried and concentrated in
vacuo. The residue was purified by chromatography on silica gel
(cyclohexane / AcOEt = 8 / 2).
1
4: IR (CHCl ): 1800, 1759, 1700. H NMR (CDCl , 300 MHz):
3
3
3.29 (dd, 1H, J = 3.0 and J = 5.1 Hz); 3.35 (dd, 1H, J = 5.4 and J =
5.1 Hz); 4.02 (d, 1H, J = 15.0 Hz); 4.4 (d, 1H, J = 15 Hz); 5.21 (m,
13
4H); 5.55 (dd, 1H, J = 3.0 and J = 5.4 Hz); 7.2-7.4 (m, 15H).
C
Scheme 4
NMR (CDCl , 75.5 MHz): 166.8; 152.4; 135.0; 134.5; 128.6;
3
128.5; 128.4; 128.2; 128.1; 127.9; 69.4; 59.9; 45.8; 45.7.
20
10: [α]
= +16.7 (CHCl , c = 0.936). IR (CHCl ): 1790, 1760,
3 3
benzyloxycarbonylamino derivatives, largely employed as β-lactam
antibiotic intermediates, is mild and quantitative.
D
1
1710, 1244. H NMR (CDCl , 300 MHz): -0.02 (s, 3H); -0.01 (s,
3
3H); 0.84 (d, 3H, J = 6.0 Hz); 0.89 (s, 9H); 3.46 (dd, 1H, J = 5.3
Hz, J = 9.5 Hz); 4.11 (d, 1H, J = 14.6 Hz); 4.13 (dq, 1H, J = 6.0
Acknowledgment: Financial support was provided by MURST (Fondi
40% and 60%) and C.N.R.
and J = 9.5 Hz); 4.86 (d, 1H, J = 14.6 Hz); 5.25 (m, 3H); 7.2-7.5
13
(m, 5H). C NMR (CDCl , 75.5 MHz): 166.1; 153.2; 152.7;
3
135.8; 134.4; 128.6; 128.5; 128.4; 127.5; 69.6; 68.5; 51.7; 51.6;
45.5; 25.9; 20.8; 17.8; -4.3; -4.6.
References and Notes:
(1) Georg, G.I.; Ravikumar, V.T. In The Organic Chemistry of β-
Lactams; Georg, G.I., Ed.; VCH Publishers, Inc.: New York,
1993; 295. Georg, G.I. In Studies in Natural Product Chemistry;
Rahman, A-ur, Ed.; Elsevier Science: Amsterdam, 1988; vol.2.
(9) Kamiya, T.; Hashimoto, M.; Nakaguchi, O.; Oku, T. Tetrahedron
1979, 35, 323.
(10) For a recent study on 4-unsubstituted β-lactams see:
Palomo, C.; Aizpurua, J.M.; Legido, M.; Galarza, R. J. Chem.
Soc., Chem. Comun. 1997, 233. Alcaide, B.; Rodriguez-Vincente,
A.; Sierra, M.A. Tetrahedron Lett. 1998, 39, 163.
(2) van der Steen, F.H.; van Koten, G. Tetrahedron 1991, 47, 7503.
Hart, D. J.; Ha, D.-C. Chem. Rev. 1989, 89, 1447. Brown, M. J.
Heterocycles 1989, 29, 2225. 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. Andreoli, P.; Billi, L.; Cainelli, G.;
Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G. Tetrahedron
1991, 47, 9061.
(11) Manhas, M. S.; Amin, S. G.; Ram, B.; Bose, A. K. Synthesis 1976,
689.
(12) To a stirred solution of benzyl amine (1mmol) in dry CH Cl (5
2
2
mL) under an inert atmosphere at rt were successively added
MgSO (2 mmol) and the (2S)-t-butyldimethylsilyloxylactal 9
4
(1mmol). The resulting mixture was stirred at room temperature
until the starting aldehyde was consumed (GC-monitoring). The
filtered solution was evaporated to give the crude imine.
(3) Cainelli, G.; DaCol, M.; Galletti, P.; Giacomini, D. Synlett 1997,
923.
(4) Fekner, T.; Baldwin, J. E.; Adlington, R. M.; Schofield, C. J. J.
Chem. Soc., Chem .Comm. 1996, 1989. Tsubouchi H.; Tsuji, K.;
Ishikawa H. Synlett 1994, 63.
(13) Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G.
Tetrahedron 1996, 52, 1685.
(14) A representative procedure is as follows:
(5) N,N-Dibenzyloxycarbonylglycine tert-butyl ester 1 was prepared
according to a modified procedure using an excess of NaH instead
of KH to prevent the formation of the N,N,N-tribenzyloxycarbonyl
amine: Takeuchi,Y.; Nabetani, M.; Takagi, K.; Hagi, T.; Koizumi,
T. J. Chem. Soc., Perkin Trans. I 1991, 49
To a solution of β-lactam 4, 7, 10 (0.17 mmol) in THF (5 mL), 5
mg of 10% Pd on activated charcoal were added. The reaction
flask was connected to a balloon containing H at the pressure of 1
atm and the reaction was monitored by TLC each 15 min. After
total consumption of the starting material (30-60 min) the Pd was
filtered off and the solution was concentrated in vacuo to afford
the monodeprotected β-lactam 11, 12, 13. When the reaction time
was extended, total deprotection was achieved.
2
(6) Schlessinger, R. H.; Nugent, R.A. J. Am. Chem. Soc. 1982, 104,
1116.
(7) The mono N-Cbz glycyl chloride has been previously applied in
cycloaddition reactions with acyclic imines but with very low
yields (11-22%). See for instance Bose, A.K.; Manhas, M.S.;
Chawla, H.P.S.; Dayal, B. J. Chem. Soc., Perkin Trans. I 1975,
1880.
With the same procedure 100 mg (0.23 mmol) of β-lactam 4 were
deprotected using 10 mg of 5% Pd on CaCO poisoned with Pb to
afford β-lactam 11. In this case no further deprotection was
3
detected even with extended reaction time.
1
(8) A representative procedure is as follows:
11: IR (CHCl ,): 3400, 1732, 1708. H NMR (CDCl , 300 MHz):
3
3
To a solution of N,N-dibenzyloxycarbonyl glycine (343 mg, 1
3.18 (dd, 1H, J = 1.9 Hz, J = 5.4 Hz); 3.42 (dd, 1H, J = 5.2 Hz, J =
mmol) in CH Cl (10 mL) at room temperature, oxalyl chloride
(1.5 mmol, 0.13 mL) was added. After the mixture was stirred for
5.2 Hz); 4.39 (m, 2H); 4.83 (m, 1H); 5.08 (s, 2H); 6.12 (m, 1H);
2
2
13
7.2-7.4 (m, 10H). C NMR (CDCl , 75.5 MHz): 166.9; 155.6;
3
3 h, the temperature was brought to –40 °C and Et N (6 mmol,
135.9; 134.7; 128.7; 128.4; 128.0; 127.7; 67.0; 57.3; 48.1; 45.9.
3
20
0.84 mL) was slowly added dropwise into the mixture. The
solution became yellow and then orange confirming that the
ketene was formed. After 30 min at low temperature one
13: IR (CHCl ,): 3300, 1761, 1749, 1725, 1253. [α]
= + 44.3
3
D
1
(CHCl , c = 3.93). H NMR (CDCl , 300 MHz): 0.012 (s, 6H);
3
3
0.93 (s, 9H); 1.14 (d, 3H, J = 6.5 Hz); 3.53 (dd, 1H, J = 4.7 Hz, J
= 4.4 Hz); 3.97 (dq, 1H, J = 6.5 Hz, J = 4.4 Hz); 4.14 (d, 1H, J =
15.3 Hz); 4.89 (d, 1H, J = 15.3 Hz); 5.08 (dd, 1H, J = 9.6 and J =
equivalent of the appropriate imine in CH Cl (3 mL) or a
2
2
previously mixed solution of hexahydrotriazine (0.33 mmol) and
BF •OEt (1 mmol) in CH Cl (5 mL) at room temperature, was
4.7 Hz); 5.12 (m, 2H); 5.64 (d, 1H, J = 9.6 Hz); 7.1-7.4 (m, 5H).
3
2
2
2
13
added dropwise. The mixture was allowed to slowly warm to
room temperature overnight. The resulting brown solution was
C NMR (CDCl , 75.5 MHz): 167.5; 155.7; 136.0; 135.4; 128.8;
3
128.5; 128.4; 128.1; 127.6; 67.7; 67.2; 61.7; 58.5; 45.7; 25.9;
21.9; 17.9; -3.3; -4.5.
diluted with CH Cl and washed with HCl (1 M, 20 mL). The
2
2