An enantioselective synthesis of 3,4-benzo-5-oxacephams

Article abstract of DOI:10.1002/ejoc.200800985

The title compounds represent an interesting group of β-lactam antibiotics and active inhibitors of β-lactamase enzymes. All these compounds have one structural feature in common, an alkoxy fragment located at C4 of the azetidin-2-one ring. The most commo

Full text of DOI:10.1002/ejoc.200800985

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800985
An Enantioselective Synthesis of 3,4-Benzo-5-oxacephams
Anna Kozioł,[a] Jadwiga Frelek,[a] Magdalena Woz´nica,[a] Bartłomiej Furman,[a] and
Marek Chmielewski*[a]
Keywords: Lactams / Asymmetric synthesis / Chiral Lewis acids / Cyclization
The title compounds represent an interesting group of β-lac- of a mezomeric acyl ammonium cation. We herein report a
tam antibiotics and active inhibitors of β-lactamase enzymes.
All these compounds have one structural feature in common,
an alkoxy fragment located at C4 of the azetidin-2-one ring.
The most common strategy for the synthesis of 4-alkoxyazet-
idinons involves intramolecular nucleophilic substitution at
C4 that leads to ring closure. Such a displacement proceeds
via the flat intermediate that suppossedly has the structure
novel and enantioselective, chiral Lewis acid mediated cycli-
zation that affords the corresponding 5-oxacepham with ex-
cellent optical and chemical yields of up to 50%. This may
suggest that the high asymmetric induction is a result of a
kinetic resolution of the initially formed racemic oxacepham.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
induction in cases where C3 of the azetidin-2-one ring is
unsubstituted and the stereogenic center is located in the
nucleophile or to the exclusive formation of the trans-func-
tionalized ring if C3 bears a substituent.
In connection with our interest in the synthesis of 5-de-
thia-5-oxacephams,[5] herein, for the first time, we report a
highly enantioselective approach to the construction of 3,4-
benzo-5-oxacephams 4. This new approach is based on the
chiral Lewis acid promoted intramolecular nucleophilic
substitution at C4 of 4-formyloxy-azetidinones 3, which
leads to ring closure (Scheme 1).
Introduction
The N-acyliminium ions are important intermediates in
organic synthesis, especially in the context of the prepara-
tion of various nitrogen-containing natural products.[1]
Such reactive intermediates can act as electron-deficient
carbocations toward weak nucleophiles, which provides use-
ful methodologies for both inter- and intramolecular car-
bon–carbon and carbon–heteroatom bond formation.[2]
The N-acyliminium ions are typically generated in acidic
media from lactams bearing a leaving group in the α-posi-
tion to the nitrogen atom. Since the middle of the 1960s,
cationic cyclization involving benzenoid, alkene or alkyne
nucleophiles, and N-acyliminium ions has found a broad
application in the synthesis of cyclic systems. However, in
noticeable contrast to numerous examples of β-lactam syn-
thesis,[3] there have only been a few examples reported of
the use of nucleophiles other than carbon-based ones in the
intramolecular addition to N-acyliminium ions.
5-Oxacephams and clavams represent an interesting
group of β-lactam antibiotics and β-lactamase inhibitors.[4]
All these compounds have one structural feature in com-
mon – an alkoxy fragment at C4 of the azetidin-2-one ring.
One of the most common strategies for the synthesis of such
compounds calls for nucleophilic substitution at C4 of azet-
idin-2-one, which can either constitute the ring closure step
or can be followed by the closure of a five- or six-membered
ring by intramolecular alkylation of the nitrogen atom. The
weak point of such a strategy relates to low asymmetric
Scheme 1. Synthetic strategy.
Racemic 3,4-benzo-5-oxacephams have been synthesized
by the base-catalyzed (NaOH or EtONa/EtOH) condensa-
tion of salicylaldehyde or o-hydroxyphenones with 4-acet-
oxyazetidinone.[6] It is likely a two-step process occurs by
nucleophilic substitution of the acetoxy group, followed by
addition of the NH group of azetidinone to the carbonyl
group of phenone (Scheme 2).[6]
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax: +48-22-632-66-81
E-mail: chmiel@icho.edu.pl
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 2. Base-catalyzed formation of substituted 3,4-benzo-5-
oxacephams.
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 338–341

An Enantioselective Synthesis of 3,4-Benzo-5-oxacephams
Table 1. Evaluation of reaction conditions.
Result and Discussion
We assumed that treatment of the N-alkylated azetid-
inone of type 3, which bears the o-hydroxybenzyl substitu-
ent at the nitrogen atom, with a chiral Lewis acid would
result in cyclization. This leads to a nonracemic 3,4-benzo-
5-oxacepham skeleton 4. Such displacement would likely
proceed via a presumed planar intermediate having an N-
acyliminium cationic structure 5 (Scheme 1). The desired
cyclization precursor 3 should be accessible from the readily
available 4-vinyloxyazetidinone (1)[7] and suitably substi-
tuted benzyl bromides 2 (Scheme 3).
Reaction of 3a in CH2Cl2 with Lewis acids such as
BF3·OEt2 or TMSOTf gave (Ϯ)-4a in a good yield. How-
ever, 3a was less prone to undergo the desired ring closure
when other acids such as SnCl4, SnCl2/TMSCl, Yb(OTf)3,
or In(OTf)3 were used. No reaction was observed with
TFA, TsOH, (PhO)3B, or Et3Al.
Entry Solvent
Temperature [°C] Time [h] Yield [%][a] ee [%][b]
1
2
3
4
5
6
CH2Cl2
CH2Cl2
CH2Cl2
toluene
Et2O
–40
–20
0
10
6
3
0
–
30
35
34
32
0
78
85
80
72
–
0
3
0
3
THF
0
10
[a] Isolated yield determined after flash chromatography on SiO2.
[b] Enantiomeric excess was determined by chiral HPLC.
Over the past few years, several examples of the enantio-
selective addition of carbon nucleophiles to the prochiral
iminium intermediates have appeared.[8] These results
prompted us to investigate whether the corresponding azet-
idinones of type 3 could be substrates in the chiral Lewis
acid catalyzed enantioselective cyclization reaction.
respectively) and excellent enantioselectivity (98 and 99%
ee, respectively). The presence of bromide at the 6- and 6Ј-
positions of the binaphthol molecule had little effect on the
chemical yield, but the enantioselectivity decreased visibly.
Application of (S,S)-TADOL 9 instead of BINOL ligands
6–8 gave a similar conversion providing ent-4a, but affected
the enantioselectivity (Table 2). In all reactions, the ligands
were recovered by column chromatography in an 80–90%
yield without loss of enantiomeric purity.
Our initial studies indicated that azetidinone 3a does not
undergo ring closure in the presence of chiral phosphoric
acids[8,9] and a variety of metal–ligand combinations.[10]
However, when 3a was stirred in CH2Cl2 in the presence of
a stoichiometric mixture of (S)-BINOL and SnCl4 at 0 °C
for 3 h,[11] the cyclization proceeded smoothly to give (+)-
4a in a 35% yield after silica gel column chromatography
(Table 1, Entry 3) with 85% ee. The reaction was carried
out until the disappearance of substrate (TLC monitored).
Note that when the reaction temperature was decreased
to –20 °C, a lower enantioselectivity was observed (Entry
2). If toluene or diethyl ether were used as the solvent, the
yield was practically unchanged, but the enantioselectivity
was reduced to 80 and 72%, respectively. There was no re-
action when THF was used as a solvent. All attempts to
reduce the ratio of substrate 3 to chiral ligand were unsuc-
cessful. The use of 0.5 equiv. of chiral acid reduced the yield
to 50% of that found for the primary experiment. Having
the first positive result, we investigated the enantioselective
cyclization under the same conditions by varying the chiral
ligands (Table 2). When either the (S)-3,3Ј-bisphenyl-BI-
NOL or the (S)-3,3Ј-bis-α-naphthyl-BINOL were em-
Table 2. Ligand evaluation studies for enantioselective formation
of 4a in the presence of 1 equiv. of ligand/SnCl4 as a catalyst
(CH2Cl2, 0 °C, 3 h).
[a] Isolated yield determined after flash chromatography on SiO2.
ployed, 4a was obtained in a moderate yield (35 and 39%, [b] Enantiomeric excess was determined by chiral HPLC.
Scheme 3. Preparation of N-benzyl-substituted azetidinones 3.
Eur. J. Org. Chem. 2009, 338–341
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
339

A. Kozioł, J. Frelek, M. Woz´nica, B. Furman, M. Chmielewski
SHORT COMMUNICATION
Subsequently, we analyzed the scope of this asymmetric exciton chirality method (ECCD) was used for this pur-
reaction with various N-benzylated azetidinones 3. As pose.[12] On the basis of the data obtained, we were able to
shown in Table 3, the enantiomeric excess as well as the assign the (6R) configuration to compound (+)-4a (Fig-
yield of products is dependent on the nature of the substitu- ure 1). Similarly, the CD data allowed the determination of
ents on the phenol ring.
the absolute configuration of the remaining compounds 4.
In a further effort to corroborate the conclusion made on
the basis of ECCD, time-dependent density functional
theory (TDDFT) calculations were used to simulate the CD
spectrum of compound 4b. As can be seen in Figure 1, the
experimental and simulated CD curves are in excellent
agreement and thus provide independent proof for the con-
figurational assignment made.
Table 3. Cyclizations of 3 in the presence of 1 equiv. of (S)-3,3Ј-bis-
α-naphthyl-BINOL 7/SnCl4 as a catalyst (CH2Cl2, 0 °C, 3 h).
Figure 1. Experimental CD spectra of ent-4a (-·-) and 4b (···) and
simulated CD spectrum of 4b (Ϫ) (left). Lowest energy conformer
of 4b calculated at the B3LYP 6-31G++ (d,p) level.
The scope of this transformation was further extended to
the intermolecular reaction, which leads to compounds of
type 12 (Scheme 4). In all cases, a moderate chemical yield
and enantioselectivity, much lower than that for the intra-
molecular process, was observed under standard cyclization
conditions. Furthermore, it was interesting to note that phe-
nols 10 react with azetidinone 11[7] in the presence of chiral
phosphoric acids[8,9] as catalyst to produce the expected 4-
phenoxy-azetidinones 12 in good yield (70–80%), but as ra-
cemic mixtures. The low asymmetric induction for the inter-
molecular process is worth mentioning as it implies that
the generation of a defined absolute configuration at C4
of azetidinone in this fashion[6] has little chance of being
successful.
[a] Isolated yield determined after flash chromatography on SiO2.
[b] Enantiomeric excess was determined by chiral HPLC. [c] (R)-
3,3Ј-bis-α-naphthyl-BINOL was used as a chiral ligand.
The low yield of the reaction in the presence of chiral
catalysts, which never exceeds 50%, may suggest that the
high asymmetric induction is a result of a kinetic resolution
of the initially formed racemic oxacepham. This mecha-
nistic proposition is strongly supported by the partial asym-
metric destruction of racemic 4a in the presence of the chi-
ral catalyst. Cepham 4a in CH2Cl2 solution in the presence
of a stoichiometric mixture of (S)-BINOL and SnCl4 at
0 °C leads to the enantiomerically enhanced compound ent-
4a in 25% yield and 56% ee after 1.5 h and in 15% yield
and 85% ee after 3 h.
Scheme 4. Intermolecular enantioselective formation of 12.
The compound 12a (17% ee) was subsequently trans-
To assign the absolute configuration at the C6 carbon
atom in compounds 4, we applied circular dichroism spec-
troscopy (CD). Building on the presence of two appropri- formed into ent-4a (17% ee) by NBS bromination of the
ately oriented chromophores in the investigated molecules, methyl group, followed by intramolecular alkylation of the
namely, an amide and a phenyl/phenoxy chromophores, the nitrogen atom (Scheme 5).
Scheme 5. Intramolecular N-benzylation leading to ent-4a.
340
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Eur. J. Org. Chem. 2009, 338–341

An Enantioselective Synthesis of 3,4-Benzo-5-oxacephams
[3] H. Wild in The Organic Chemistry of β-Lactams (Ed.: G. I.
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In conclusion, for the first time, an enantioselective ap-
proach to the synthesis of oxygen analogues of cephalospo-
rins is described. The key step of the method is based on
the chiral Lewis acid mediated, intramolecular alkylation of
a phenol hydroxy group by the N-acyliminium ion gener-
ated from the 4-formyloxyazetidinone fragment. However,
the mechanism of the reaction requires further studies. It is
important to note that while the chiral complex has to be
used in a stoichiometric amount, the chiral ligand could
easily be recovered from the post-reaction mixture for reuse
without any appreciable loss of enantiomeric purity of the
product.
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Experimental Section
˙
Typical Procedure for Enantioselective Formation of 4: Solution of
7 (75 mg, 0.14 mmol, 1.0 equiv.) in CH2Cl2 (5 mL) at 0 °C was
treated with a 1  solution of SnCl4 in CH2Cl2 (140 µL, 1 equiv.)
under argon. After 15 min, compound 3a (31 mg, 0.14 mmol) was
added. The reaction mixture was stirred for 3 h (disappearance of
substrate, TLC monitored) and diluted with saturated NaHCO3
(5 mL). The aqueous phase was extracted with CH2Cl2
(3ϫ10 mL). The organic extracts were combined and dried with
MgSO4. The solution was filtered, and the filtrate evaporated. The
crude product was purified by column chromatography (silica gel,
7:3 hexanes/methyl-tert-butyl ether) to yield 9.6 mg (0.055 mmol)
of 4a as a yellow liquid. Yield: 39%, 99% ee. 1H NMR (500 MHz,
CDCl3): δ = 3.02 (d, J = 15.0 Hz, 1 H, CH2), 3.36 (ddd, J = 15.0,
3.0, 2.1 Hz, 1 H, CH2), 4.21 (d, J = 16.4 Hz, 1 H, CH2–N), 4.57
(d, J = 16.4 Hz, 1 H, CH2–N), 5.27 (d, J = 3.0 Hz, 1 H, CH–O),
6.94 (d, J = 8.2 Hz, 1 H, 4-H), 7.00 (tm, J = 7.6 Hz, 1 H, 3-H),
7.07 (d, J = 7.6 Hz, 1 H, 5-H), 7.20 (tm, J = 8.2 Hz, 1 H, 5-H)
ppm. 13C NMR (CDCl3): δ = 38.9 (CH2N), 46.3 (CH2), 75.3 (CH–
O), 117.8 (C-1), 118.4 (C-3), 122.4 (C-5), 127.2 (C-4), 128.5 (C-6),
152.2 (C-2), 167.3 (C=O) ppm. MS (HR-ESI): calcd. for
C10H10NO2 [M+ H]+ 176.0706; found 176.0697. C10H9NO2
(175.18): calcd. C 68.56, H 5.18, N 8.00, O 18.27; found C 68.59,
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tested. In all cases, the expected 3,4-benzo-5-oxacephams were
formed in very low yields, as racemic mixtures.
H 5.20, N 8.03. IR (film): ν = 1774 cm–1. [α]26 = +36 (c = 0.02,
˜
D
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Supporting Information (see footnote on the first page of this arti-
cle): Detailed procedures and spectroscopic data of cyclization pre-
cursors and 3,4-benzo-5-oxacephams are presented.
Acknowledgments
This work was supported by the Ministry of Education and Sci-
ence, grant PBZ-KBN-126/T09/08/2004.
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Received: October 10, 2008
Published Online: December 9, 2008
Eur. J. Org. Chem. 2009, 338–341
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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