A practical preparation of the key intermediate for penems and carbapenems synthesis

Article abstract of DOI:10.1038/ja.2013.8

A novel, practical and stereoselective synthesis of (3R,4R)-4-acetoxy-3-(R) -1-(t-butyldimethylsilyloxy)ethyl-2-azetidinone, a key intermediate in the preparation of β-lactam antibiotics is reported. The crucial step of the synthesis is based on the Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade between silyl protected (R)-3-butyn-2-ol and the nitrone derived from benzyl hydroxylamine and benzyl glyoxylate. The obtained adduct is subjected to debenzylation with sodium, or lithium in liquid ammonia followed by oxidation with lead tetraacetate to afford the final product.

Full text of DOI:10.1038/ja.2013.8

The Journal of Antibiotics (2013) 66, 161–163
2013 Japan Antibiotics Research Association All rights reserved 0021-8820/13
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ORIGINAL ARTICLE
A practical preparation of the key intermediate
for penems and carbapenems synthesis
Barbara Grzeszczyk, Sebastian Stecko, Łukasz Mucha, Olga Staszewska-Krajewska, Marek Chmielewski
and Bartłomiej Furman
A novel, practical and stereoselective synthesis of (3R,4R)-4-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone, a key
intermediate in the preparation of b-lactam antibiotics is reported. The crucial step of the synthesis is based on the Cu(I)-
mediated Kinugasa cycloaddition/rearrangement cascade between silyl protected (R)-3-butyn-2-ol and the nitrone derived from
benzyl hydroxylamine and benzyl glyoxylate. The obtained adduct is subjected to debenzylation with sodium, or lithium in liquid
ammonia followed by oxidation with lead tetraacetate to afford the final product.
The Journal of Antibiotics (2013) 66, 161–163; doi:10.1038/ja.2013.8
Keywords: b-lactams; Kinugasa reaction; penems and cabapenems synthesis
INTRODUCTION
A relatively short route to azetidinone 1 has been reported by
Penems and carbapenems are important b-lactam antibiotics that Ohashi of Kanegafuchi Chemical Industries.10–12 The initial (R)-3-
continuously provoke interest within academic and pharmaceutical hydroxybutyrate was transformed into terminal trimethylsilyl-vinyl
laboratories.1,2 They show excellent activities against both Gram- ether that subsequently was subjected to [2 þ 2] cycloaddition with
positive and Gram-negative bacteria, while being resistant towards chlorosulfonyl isocyanate to afford the target azetidinone 1.
hydrolysis by most b-lactamases.3
Another interesting approach was described by Tatsuta et al.13
A common key intermediate for their synthesis is 4-acetoxyazeti- detailing the synthesis of azetidinone 1 from methyl 6-deoxy-
dinone 1 (Scheme 1).4 This molecule contains three stereogenic glucosamine.
centers and a AcO group at the C-4 position of the four-membered
b-lactam ring. The AcO group can be easily substituted by a variety of
nucleophiles.4 These structural features lay the foundation for the
possibility of transforming azetidinone 1 into an array of penem and
carbapenem antibiotics.4,5
Azetidinone 1 has been obtained by diverse chiral approaches.4,5
The earliest references to azetidinone 1 originated from Sankyo Co.
Ltd., and employed penicillanate esters as the chiral source.6 However,
the most convenient method for the preparation of azetidinone 1 is
the asymmetric [2 þ 2] cycloaddition of a diketene with chiral imines
derived from various chiral pools, including ethyl (S)-lactate,7
L-menthyl glyoxylate,8 and D-mannitol.9
RESULTS AND DISCUSSION
Recently, we have reported direct and simple approach to the formation
of the basic skeleton of carbapenams14–17 and N,4-diaryl substituted b-
lactam18 frameworks via diastereoselective copper(I)-mediated reaction
between nitrones and terminal acetylenes. In most cases, reactions
displayed high diastereoselectivity leading to one dominant product.19
Herein, we describe a short, high yielding and stereoselective synthesis
of azetidinone 1 in which the pivotal step, the formation of 2-
azetidinone ring, is Cu(I)-mediated Kinugasa cycloaddition/rearrange-
ment cascade between terminal acetylene 2 and nitrone, 3 which is
derived from benzyl glyoxalate and N-benzyl hydroxylamine (Scheme 2).
Scheme 1 Azetidinone 1 as a building block for synthesis of beta-lactam
antibiotics.
Scheme 2 Retrosynthetic analysis.
Institute of Organic Chemistry of Polish Academy of Sciences, Warsaw, Poland
Correspondence: Professor B Furman, Institute of Organic Chemistry of Polish Academy of Sciences, Kasprzaka 44/52, Warsaw 01-224, Poland.
E-mail: bartlomiej.furman@icho.edu.pl
This work is dedicated to Professor Kuniaki Tatsuta commemorating his 101 total synthesis.
Received 26 November 2012; revised 9 January 2013; accepted 11 January 2013

Penems and carbapenems synthesis
B Grzeszczyk et al
162
Scheme 3 Synthesis of azetidinone 1.
t
The reaction proceeds in acetonitrile under our standard condi- 2.0Hz), 2.57 (1H, d, J 2.0 Hz), 1.41 (3H, d, J 6.4 Hz, CH3), 0.9 (s, 9H, Bu),
0.13 (s, 3H, SiCH3), 0.12 (s, 3H, SiCH3).
tions to provide azetidinone 4 in 73% yields as a mixture of two
diastereomers cis-4 and trans-4 in a ratio of B3:1, respectively. The
proportion of cis/trans diastereomers of azetidinone 4 was determined
by 1H NMR. Nitrone 3 exists in solution as an easily convertible
mixture of Z and E isomers in a ratio, which is solvent dependent.20
One can assume that the first step in Kinugasa cascade, 1,3-dipolar
cycloaddition, proceeds preferentially with more reactive rotamer.
Our earlier observations of Kinugasa reaction between acetylene 2 and
non-chiral nitrones suggested that b-lactam (S)-configuration should
be obtained at the C-3 carbon atom.14 Formation of a relatively large
amount of trans isomer (trans-4) could be due to base catalyzed
epimerization of the initially formed cis-4, which can occur under
these reaction conditions. Consequently, cis (4R) and trans (4R)
substituted b-lactams are assigned. Correct configurational
assignments were proved at the end of the synthesis by comparison
with target product with known, commercially available samples of
azetidinone 1.
Benzyl gloxalate
A 500-ml, one-necked round-bottomed flask (equipped with nitrogen inlet)
was charged with dibenzyl L-tartrate (17.3g, 52.4mmol) and 300 ml of
anhydrous ethyl ether. To the resulting solution periodic acid dihydrate was
added (11.9 g, 52.4mmol). The slurry was stirred at 231C for 1.5 h during
which a white precipitate had formed. The solution was filtered through Celite
(washing with 70ml diethyl ether) and the filtrate was concentrated in vacuo
(not to dryness) to give benzyl glyoxylate, which was used without any further
purification. 1H NMR (600 MHz, C6D6) d: 8.86 (s, 1H), 7.27–7.45 (m, 5H),
5.10 (s, 2H).
Nitrone 3
Benzyl glyoxalate (7.34 g, 56.9mmol) was dissolved in MeOH (60 ml) and
anhydr. AcONa (6.07 g, 74.0 mmol) was added at room temperature. Next, a
solution of N-benzylhydroxylamine hydrochloride (9.08 g, 56.9 mmol) in
MeOH (20 ml) was added dropwise. After 2 h, MeOH was removed and the
residue was partitioned between CH2Cl2 (100ml) and water (30 ml). The
organic phase was dried over MgSO4 and then the solvent was removed to give
The isomeric mixture 4 was subjected to sodium or lithium
reduction in liquid ammonia to provide acid 5 in 98% yield, as a 3 (14.5 g) as a white solid. The solid was recrystallized from hexanes/CH2Cl2
mixture to provide 12 g (yield 78%) of nitrone 3 as colorless crystals. M.p.
105–106 1C; 1H NMR (600 MHz, CD3CN) d: 7.30–7.15 (m, 10H), 5.18 (s, 2H),
5.00 (s, 2H) 2.15 (s, 1H).
mixture of diastereomers (Scheme 3). Acid 5 was subsequently oxidized
by treatment with Pb(OAc)4 in AcOH21 to provide the desired
azetidinone 1 in 73% yield, with only minute amounts of the by-
product 6 observed. Oxidation of acid 5 proceeds with transformation
of both cis and trans isomers into acetate 1 possessing a trans
substituted ring. Azetidinone 1 displays the same analytical and
spectral data as commercially available (3R,4R)-4-acetoxy-3-[(R)-1-
(t-butyldimethylsilyloxy)ethyl]-2-azetidinone (Aldrich, Cat. no. 375845
[CAS 76855-69-1]).
Azetidinone 4
Triethylamine (0.56 ml, 4.0 mmol) was added to a suspension of CuI (190 mg,
1.0mmol) in degassed MeCN (4ml). Subsequently, the mixture was cooled to
0 1C and acetylene 2 (184mg, 1.0 mmol) in MeCN (1ml) was added. After
15 min, a solution of nitrone 3 (404 mg, 1.5mmol) in MeCN (5ml) was added
slowly. The mixture was kept at 0 1C for an additional 15min. After removal of
the cooling bath, the mixture was stirred at ambient temperature under an
inert atmosphere for 24h. The progress of the reaction was monitored by TLC.
Removal of the solvent gave a residue, which was chromatographed on silica
gel (hexane/AcOEt 4:1 v/v) to afford a mixture of azetidinones cis-4 and
trans-4 in ratio 3:1 (323mg, 71%, according to 1H NMR of crude reaction
mixture). cis-4: 1H NMR (600MHz, C6D6) d: 7.10–6.94 (10H, m, Ar), 5.06
(1H, ABq, J 12.2Hz, CH2 Ph), 4.93 (1H, ABq, J 12.2Hz CH2 Ph), 4.76 (1H,
ABq, J 15.4Hz, NCH2Ph), 4.29 (1H, ddd, J 3.6, 6.6, 13.0Hz, H-5), 4.15 (1H,
ABq, J 15.4Hz, NCH2Ph), 3.59 (1H, d, J 5.8 Hz, H-4), 2.81 (1H, dd, J 3.6,
5.8Hz, H-3), 1.10 (3H, d, J 6.6 Hz, CH3), 0.96 (9H, s, t-Bu), 0.48 (3H, s,
SiCH3), 0.16 (3H, s SiCH3); 13C NMR (150MHz, C6D6) d: 169.1, 165.9, 135.7,
135.5, 66.4, 65.0, 64.5, 62.0, 52.6, 44.6, 25.73, 25.66, 21.6, 20.7, 18.0, ꢀ0.4,
ꢀ4.6, ꢀ5.04; IR (CH2Cl2) v: 2929, 1766, 1257, 1197, 837 cmꢀ1. trans-4: 1H
NMR (600MHz, C6D6 ) d: 4.86 (1H, ABq, J 12.2 Hz, CH2Ph), 4.74 (1H, ABq, J
12.2 Hz CH2 Ph), 4.61 (1H, ABq, J 14.9Hz NCH2Ph), 4.12 (1H, ABq, J 14.9Hz
NCH2Ph), 4.12 (1H, d, J 2.6, H-4), 4.00 (1H, ddd, J 3.6, 6.3, 12.6 Hz, H-5),
3.01 (1H, dt, J 0.7, 3.3 Hz, H-3), 0.94 (3H, d, J 6.2 Hz, CH3), 0.84 (9H, s, t-Bu),
0.16 (3H, s, SiCH3), ꢀ0.04 (3H, s, SiCH3); 13C NMR (150MHz, C6D6) d:
170.5, 165.4, 135.5, 135.4, 65.4, 64.5, 63.6, 62.5, 52.0, 45.2, 25.6, 22.1, 20.7,
17.8, ꢀ4.9, ꢀ4.9; HR MS (ESI) m/z calcd for [Mþ Na]þ C26H35NO4NaSi:
476.2228; Found: 476.2236; anal calcd for C26H35NO4Si (%): C, 68.84, H, 7.78,
N, 3.09; Found C, 68.87, H, 7.79, N, 3.19.
Bearing in mind readily available starting materials 2 and 3, as well
as three simple steps toward azetidinone 1, the reported synthesis
offers some advantages over many so far reported.
EXPERIMENTAL PROCEDURE
1H and 13C NMR spectra were recorded on Varian VN MRS Spectrometer
(Varian Inc., St. Clara, CA, USA) at 600 and 150 MHz, respectively, in CDCl3
or C6D6 with tetramethylsilane (TMS) as an internal standard. Chemical shifts
are reported as d values in p.p.m., and coupling constants are in hertz. IR
spectra were recorded on a FT-IR-1600 Perkin-Elmer spectrophotometer
(Perkin Elmer, Waltham, MA, USA). Optical rotation was recorded on Jasco
P-2000 polarimeter (Jasco Inc., Easton, MD, USA). High-resolution mass
spectra were recorded on Synapt G2-S Waters Spectrometer for ESI. (R)-( þ )-
3-Butyn-2-ol and dibenzyl L-tartrate were purchased from TCI Europe
(Zwijndrecht, Belgium).
Acetylene 2
Tert-butyldimethylchlorosilane (TBSCl) (0.828 g, 5.5 mmol) was added por-
tionwise to a solution of (R)-( þ )-3-butyn-2-ol (0.350g, 5.0 mmol) and
imidazole (0.374g, 5.5 mmol) in dry CH2Cl2. After 2 h, the mixture was
diluted with CH2Cl2 (10 ml) and washed with water (5ml). The organic phase
was dried over anhydr. Na2SO4 and the solvent was removed under slightly
diminished pressure (383 hPa). The residue was dissolved in pentanes and
filtered through a short silica gel pad to afford acetylene 2 (0.828g, 90%). [a]D
þ 46.2 (c 1, CH2Cl2) 1H NMR (600 MHz, CDCl3) d: 4.51 (1H, dq, J 6.4,
Azetidinone 5
A solution of azetidinone 4 (150mg, 0.33 mmol) in tetrahydrofurane (THF)
(2ml) was added to a cooled to ꢀ78 1C mixture of lithium (36 mg,
The Journal of Antibiotics

Penems and carbapenems synthesis
B Grzeszczyk et al
163
4.06 mmol) in dry liquid NH3. After 25min, the reaction was quenched by
addition of solid NH4Cl (0.825g). The reaction mixture was gradually warmed
to ambient temperature. Next, CH2Cl2 (41 ml) was added and the resulting
solid was filtered off. After removal of solvent, the residue was dissolved in
Et2O-water mixture (1:1). The aqueous solution was lyophilized to afford a
mixture of cis-5 and trans-5 (88 mg, 98%, ratio 3:1) as a white solid. cis-5: 1H
NMR (600MHz, D2O) d: 4.16 (1H, ddd, J 5.1, 11.3Hz, H-5), 4.05 (1H, d, J
5.8 Hz, H-4), 3.49 (1H, dd, J 5.8, 5.2Hz, H-3), 1.14 (3H, d, J 6.4 Hz, CH3),
0.74 (9H, s, Sit-Bu), 0.01 (3H, s, SiCH3), 0.02 (3H, s, SiCH3); 13C NMR
(150 MHz, D2O) d: 176.1, 171.8, 65.5, 60.1, 53.0, 25.4, 25.1, 21.3, 20.4, 17.5, –
5.05, –5.55. trans-5: 1H NMR (600 MHz, D2O) d: 4.22 (1H, ddd, J 2.8, 6.4,
12.8 Hz, H-5), 4.02 (1H, d, J 2.3 Hz, H-4), 3.06 (1H, t, J 2.6 Hz, H-3), 1.15
(3H, d, J 6.4 Hz, CH3), 0.74 (9H, s, Sit-Bu), 0.01 (3H, s, CH3), 0.02 (3H, s,
CH3), MS (ESI): [Mþ Na] þ 296.1; MS (ESI): [MꢀH]ꢀ 272.2, [Mþ
HCOO]ꢀ 318.1.
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To a solution of azetidinones 5 (90 mg, 0.331mmol) in dry N,N-dimethylfor-
mamide (DMF) (1.7ml), AcOH (322ml) and Pb(OAc)4 (219mg, 0.494 mmol)
was added. After 3 h, DMF and AcOH were removed under diminished
pressure and the residue was treated with Et2O (15 ml). The remaining solids
were removed and the solvent was evaporated to provide azetidinone 1 (15 mg,
73%). Mp. 105–107 1C [Lit. 107–109 1C, (Aldrich, Cat. no. 375845 [CAS
76855-69-1])]; [a]D þ 51.7 (c 0.4, CHCl3) [Lit. [a]D þ 51 (c 1, CHCl3),
(Aldrich, Cat. no. 375845 [CAS 76855-69-1])]; 1H NMR (600 MHz, C6D6) d:
5.74 (1H, d, J 1.0 Hz, H-4), 5.70 (1H, bs, NH), 3.89 (1H, ddd, J 3.8, 6.3,
12.6 Hz, H-5), 2.87 (1H, dd, J 1.0, 3.8Hz, H-3), 1.50 (3H, s, OAc), 0.99 (3H, d,
J 6.3 Hz, CH3), 0.90 (9H, s, t-BuSi), 0.06 (3H, s, CH3Si), ꢀ0.04 (3H, s, CH3Si);
13C NMR (150MHz, C6D6) d: 170.1, 165.7, 75.1, 65.3, 64.1, 25.6, 21.9, 19.9,
17.8, ꢀ4.7, ꢀ5.3. HR MS (ESI) m/z calcd for C13H25NO4SiNa [Mþ Na]þ
310.1451; found 310.1459.
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ACKNOWLEDGEMENTS
The authors are grateful to the European Union within European Regional
Development Fund (Project POIG.01.01.02.-14-102/09) for financial support
of research.
The Journal of Antibiotics