Regioselective Baeyer-Villiger Oxidation in 4-Carbonyl-2-azetidinone Series: A Revisited Route toward Carbapenem Precursor

Article abstract of DOI:10.1021/jo030377y

A novel synthesis of acetoxyazetidinone 2 is presented. The azetidinone ring of compounds 7 is formed by C-3/C-4 cyclization of (2R,3R)-epoxybutyramide precursors 6, N-protected with a benzhydryl group. N-Deprotection by photoactivated bromination and acidic treatment leads to compounds 10 with various CO-R substituents at C-4. Transformation of these substituents by Baeyer-Villiger oxidation gives the desired regioisomer 11 with the cyclopropyl side-group which is the only group (among R = H, Ph, t-Bu, i-Pr, c-Pr) able to satisfy both the steric requirements of the cyclization step and the electronic requirements of the oxidative rearrangement step.

Full text of DOI:10.1021/jo030377y

SCHEME 1. Gen er a l Retr osyn th esis of th e
Ca r ba p en em F a m ily
Regioselective Ba eyer -Villiger Oxid a tion
in 4-Ca r bon yl-2-a zetid in on e Ser ies: A
Revisited Rou te tow a r d Ca r ba p en em
P r ecu r sor
Mathieu Laurent,† Marcel Ce´re´siat,‡ and
J acqueline Marchand-Brynaert*,†
Unite´ de Chimie organique et me´dicinale,
Universite´ catholique de Louvain, Baˆtiment Lavoisier,
Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium,
and Tessenderlo Chemie s.a./ n.v., Rue du Troˆne 130,
B-1050 Bruxelles, Belgium
The B-V method, relatively mild and avoiding the use
of toxic metals, is of potential industrial interest. Since
the azetidinyl function could stabilize a partial positive
charge created in C-4, this structural motive should be
a good migrating group in electron-deficient rearrange-
ments, such as the B-V oxidation.10,11 However azetidinyl
as migrating group was scarcely studied. The reaction
has been mainly described with two types of precursors,
4-methylcarbonyl-8a-c and 4-phenylcarbonyl-2-azetidi-
nones8d-g (methyl and phenyl substituents are known to
be bad migrating groups). Alcaide et al.,8h,i in a work
about 4-formyl-2-azetidinone, showed that azetidinyl
migrated preferentially also over hydrogen; this is quite
surprising because the B-V reaction is a common way
to transform aldehyde into carboxylic acid (migration of
hydrogen).8h
marchand@chim.ucl.ac.be
Received December 10, 2003
Abstr a ct: A novel synthesis of acetoxyazetidinone 2 is
presented. The azetidinone ring of compounds 7 is formed
by C-3/C-4 cyclization of (2R,3R)-epoxybutyramide precur-
sors 6, N-protected with a benzhydryl group. N-Deprotection
by photoactivated bromination and acidic treatment leads
to compounds 10 with various CO-R substituents at C-4.
Transformation of these substituents by Baeyer-Villiger
oxidation gives the desired regioisomer 11 with the cyclo-
propyl side-group which is the only group (among R ) H,
Ph, t-Bu, i-Pr, c-Pr) able to satisfy both the steric require-
ments of the cyclization step and the electronic requirements
of the oxidative rearrangement step.
In revisiting the synthesis of acetoxyazetidinone 2
developed by Hanessian et al.,8g we were confronted with
(5) (a) Reider, P. J .; Grabowski, E. J . J . Tetrahedron Lett. 1982, 23,
2293. (b) Cainelli, G.; Contento, M.; Giacomini, D.; Panunzio, M.
Tetrahedron Lett. 1985, 26, 937. (c) Bonini, C.; Di Fabio, R. Tetrahedron
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Tetrahedron Lett. 1988, 29, 1409. (c) Mori, M.; Kagechika, K.; Sasai,
H.; Shibasaki, M. Tetrahedron 1991, 47, 531.
(7) (a) Murahashi, S.-I.; Naota, T.; Kuwabara, T.; Saito, T.; Kumo-
bayashi, H.; Akutagawa, S. J . Am. Chem. Soc. 1990, 112, 7820. (b)
Takao, S.; Hidenori, K.; Shunichi, M. Eur. Pat. 488.611 A1, 1990. (c)
Takao, S.; Hidenori, K.; Shunichi, M. Eur. Pat. 509.821 A1, 1991.
(8) For some examples of Baeyer-Villiger oxidation of 4-methyl-
carbonylazetidinones, see: (a) Shiozaki, M.; Ishida, N.; Maruyama, H.;
Hiraoka, T. Tetrahedron 1983, 39, 2399. (b) Ito, Y.; Kobayashi, Y.;
Kawabata, T.; Takase, M.; Terashima, S. Tetrahedron 1989, 45, 5767.
(c) Arrieta, A.; Lecea, B.; Cossio, F. P.; Palomo, C. J . Org. Chem. 1988,
53, 3784. For some examples of Baeyer-Villiger oxidation of 4-phen-
ylcarbonylazetidinones, see: (d) Altamura, M.; Ricci, M. Synth. Com-
mun. 1988, 18, 2129. (e) Shiozaki, M. Synthesis 1990, 691. (f)
Murahashi, S.-I.; Oda, Y.; Naota, T. Tetrahedron Lett. 1992, 33, 7557.
(g) Hanessian, S.; Bedeschi, A.; Battistini, C.; Mongelli, N. J . Am.
Chem. Soc. 1985, 107, 1438. For Baeyer-Villiger oxidation of 4-formyl-
azetidinones, see: (h) Alcaide, B.; Aly, M. F.; Sierra, M. A. J . Org.
Chem. 1996, 61, 8819. (i) Alcaide, B.; Aly, M. F.; Sierra, M. A.
Tetrahedron Lett. 1995, 36, 3401.
Carbapenems 1 form a growing class of â-lactam
antibiotics1 that occupies a central role in the fight
against bacteria resistant to â-lactam antibiotics of the
previous generations.2 They show excellent activities
against both Gram-positive and Gram-negative bacteria,
and they are resistant to hydrolysis by most of â-lacta-
mases.3
A common key intermediate of their synthesis is
acetoxyazetidinone 2 (Scheme 1).4 This molecule contains
three of the four stereocenters of the final compounds and
a leaving group in the C-4 position allowing further
alkylation. Several methods to introduce an acetoxy
group in this position have been carried out, on various
azetidinone precursors, including oxidative substitution
with Pb(OAc)4,5 electrochemical oxidation,6 Ru-catalyzed
oxidation,7 Baeyer-Villiger (B-V) oxidative rearrange-
ment,8 and others.9
* Corresponding author: Tel: + 32-10-472740. Fax: + 32-10-474168.
† Universite´ catholique de Louvain.
(9) (a) Nakatsuka, T.; Iwata, H.; Tanaka, R.; Imajo, S.; Ishiguro,
M. J . C. S. Chem. Commun. 1991, 662. (b) Kita, Y.; Shibata, N.; Miki,
T.; Takemura, Y.; Tamura, O. J . C. S. Chem. Commun. 1990, 727. (c)
Easton, C. J .; Love, S. G. Tetrahedron Lett. 1986, 27, 2315. (d) Easton,
C. J .; Love, S. G.; Wang, P. J . Chem. Soc., Perkin Trans. 1 1990, 277.
(e) Lynch, J . E.; Laswell, W. L.; Volante, R. P.; Reamer, R. A.; Tschaen,
D. M.; Shinkai, I. Heterocycles 1993, 35, 1029.
(10) For reviews about the Baeyer-Villiger reaction, see: (a) Renz,
M.; Meunier, B. Eur. J . Org. Chem. 1999, 737, 7. (b) Krow, G. R.
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 7, p 671. (c) Krow, G. R. Organic Reactions; Paquette,
L. A., Ed.; J ohn Wiley & Sons: New York, 1993; Vol. 43, p 251.
(11) Migratory aptitude is related to the ability of a group to stabilize
a positive charge in the transition state: (a) Smith, P. A. S. In Molecular
Rearrangements; De Mayo, P., Ed.; J ohn Wiley and Sons: New York,
1963; pp 457-592. (b) Hawthorne, M. F.; Emmons, W. D.; McCallum,
K. S. J . Am. Chem. Soc. 1958, 80, 6393.
‡ Tessenderlo Chemie.
(1) (a) The Chemistry of â-Lactams; Page, M. I., Ed.; Chapman &
Hall: London, 1992. (b) Kim, O. K.; Fung-Tomc, J . Expert Opin. Ther.
Patents 2001, 11, 1267.
(2) For recent reviews on bacterial resistance, see: (a) Walsh, C.
Nature 2000, 406, 775. (b) Mascaretti, O. A. Bacteria versus Antibacte-
rial Agents; ASM Press: Washington, DC, 2003. (c) Walsh, C. Antibiot-
ics: Actions, Origins, Resistance; ASM Press: Washington, DC, 2003.
(3) For reviews on â-lactamases, see: (a) Matagne, A.; Dubus, A.;
Galleni, M.; Fre`re, J .-M. Nat. Prod. Rep. 1999, 16, 1. (b) Page, M. I.;
Laws, A. P. Chem. Commun. 1998, 1609. (c) Massova, I.; Mobashery,
S. Acc. Chem. Res. 1997, 30, 162. (d) Fre`re, J .-M. Mol. Microbiol. 1995,
16, 385. (e) Mascaretti, O. A.; Boschetti, C. E.; Danelon, G. O.; Mata,
E. G.; Roveri, O. A. Curr. Medicin. Chem. 1995, 1, 441.
(4) Berks, A. H. Tetrahedron 1996, 52, 331.
10.1021/jo030377y CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/26/2004
3194
J . Org. Chem. 2004, 69, 3194-3197

SCHEME 2. Syn th esis of P r ecu r sor sa
the enolate oxygen. The side group R also played a crucial
role: t-Bu showed better results than Ph (azetidinone was
practically the only product). The relative importance of
steric over electronic effects of the R substituent could
not be determined. However, in preliminary experiments,
we recorded similar results with R ) Ph and R )
o-MeOPh, indicating almost no influence of electronic
effects.
At this stage of our research, several questions re-
mained in order to efficiently achieve the synthesis of
acetoxyazetidinone 2: what is the steric influence of the
R substituents on the C-3/C-4 cyclization step; what is
the migrating ability of the azetidinyl moiety versus these
R groups in the following B-V step; and finally, are the
structural requirements for making these two steps well
compatible?
a
Reagents and conditions: (i) 4a , benzhydrylbromide, neat, 70
This paper discloses our original solution to those
questions and thus proposes a synthesis of the carbap-
enems precursor 2 which could be possibly developed on
a large scale.
°C, 5 h, 76%; (ii) 4b-e, benzhydrylamine, K2CO3, KI, DMF, reflux,
overnight, 80-100%; (iii) 3, (COCl)2, pyridine, THF, -5 °C, 3 h,
70-85%; (iv) CF3CO2H, CHCl3, H2O, rt, 3 h, 98%.
SCHEME 3. Cycliza tion Step w ith O- a n d
C-Alk yla tion P r od u cts
To study the influence of the side group R (R ) Ph,
t-Bu, i-Pr, c-Pr), we synthesized the intermediates 6b-e
(Scheme 2). They were available in two steps from
benzhydrylamine, the corresponding R-bromoketones
4b-e,14 and the chiral epoxybutanoate 315 derived from
L-threonine. The formation of the secondary amines
5b-e required the alkylation of 4b-e in basic conditions
in the presence of potassium iodide to afford yields in
the 80-100% range. Epoxyamides 6b-e were synthe-
sized by coupling amines 5b-e with carboxylate 3
activated in situ with oxalyl chloride. The isolated
products (70-85% yield) showed the typical splitting of
1
all the H NMR signals due to the restricted rotation of
the amide bond and the characteristic AB-system of the
CH2 near the amide. The synthesis of aldehyde 6f (R )
H) needed to work with protected intermediates (Z )
(OMe)2). The aminodimethylketal 4a was alkylated with
benzhydrylbromide to furnish 5a which was coupled to
epoxide 3 as before. The resulting precursor 6a (69%
yield) was then quantitatively deprotected with TFA,
giving 6f (Scheme 2).
Cyclization of compounds 6b-f under the best condi-
tions previously established (LiHMDS, THF, 0 °C) showed
a clear influence of the bulkiness of the C-4 side group
(Scheme 3, Table 1). Whereas R groups such as t-Bu, i-Pr,
and c-Pr allowed exclusive or predominant formation of
the azetidinone product (C-alkylation), the Ph group gave
moderate yield and the H substituent gave only traces
of azetidinone 7f (visible in 1H NMR at 9 ppm for
aldehyde proton). The O-alkylation product 8f was formed
almost quantitatively. By changing the cyclization condi-
tions (Hanessian’s conditions), a mixture of six- and
seven-membered heterocycles 8f and 9f was recovered,
as in the case of 6b cyclization where R ) Ph.
the question of migrating ability of the azetidinyl group
versus secondary and tertiary alkyl groups. The Hanes-
sian’s strategy was based on the C-3/C-4 ring closure for
the formation of the â-lactam ring from (2R,3R)-epoxy-
butyramide precursors (Scheme 2). In these intermedi-
ates, we replaced the initial p-anisyl N-protective group
by a benzhydryl moiety because this former protection
required supra-stoichiometric amounts of ceric salt (CAN)
for cleavage, a toxic reagent which waste products cause
environmental problems at the industrial scale. Our new
protective group imposed to develop an original and clean
deprotection method,12 based on photoactivated bromi-
nation of the benzhydryl carbon and subsequent smooth
hydrolysis.
The use of the benzhydryl protective group also changed
the steric and electronic requirements of the C-3/C-4
cyclization step. Due to its bulkiness, O-alkylation versus
the required C-alkylation could be favored (Scheme 3),
depending on the experimental conditions. We previously
studied the influence of the strength of the base showing
that kinetic conditions are needed to maximize the
azetidinone yield.13 A small countercation disfavored
O-alkylation, probably by forming a strong ionic pair with
Azetidinones 7b-e were isolated by column chroma-
tography and characterized by NMR spectroscopy; the
(12) (a) Ce´re´siat, M.; Belmans, M.; Marchand-Brynaert, J .; Laurent,
M. Eur. Pat. EP01870100.3, 2001. (b) Laurent, M.; Belmans, M.;
Kemps, L.; Ce´re´siat, M.; Marchand-Brynaert, J . Synthesis 2003, 570.
(c) Tinant, B.; Laurent, M.; Ce´re´siat, M.; Marchand-Brynaert, J . Z.
Kristallogr. NCS 2003, 218, 145.
(13) Deng, B.-L.; Demillequand, M.; Laurent, M.; Touillaux, R.;
Belmans, M.; Kemps, L.; Ce´re´siat, M.; Marchand-Brynaert, J . Tetra-
hedron 2000, 56, 3209.
(14) 4a -c are commercially available; 4d ,e are synthesized following
published procedures: (a) Gaudry, M.; Marquet, A. Org. Synth. 1976,
VI, 193. (b) Calverley, M. J . Tetrahedron 1987, 43, 4609.
(15) (a) Yanagisawa, H.; Ando, A.; Shiozaki, M.; Hiraoka, T.
Tetrahedron Lett. 1983, 24, 1037. (b) Petit, Y.; Sanner, C.; Larcheveˆque,
M. Synthesis 1988, 538. (c) Demillequand, M.; Ce´re´siat, M.; Belmans,
M.; Kemps, L.; Marchand-Brynaert, J . J . Chromatogr. A 1999, 832,
259.
J . Org. Chem, Vol. 69, No. 9, 2004 3195

TABLE 1. Ra tio (%) of Cycliza tion P r od u cts
Deter m in ed by 1H NMR on th e Cr u d e Mixtu r es
TABLE 2. Ra tio (%) of B-V P r od u cts Deter m in ed by 1H
NMR on th e Cr u d e Mixtu r es
R
7
8
9
R
11
12
Ph
57
23
0
15
20
0
0
Ph8d-g
t-Bu
i-Pr
100
0
52
0
t-Bu
i-Pr
c-Pr
H
100 (64)
85 (58)
92 (82)
2 (0)
100
48
0
8 (7)
0
0
c-Pr
100
98 (84)
0
74 (45)a
26 (13)a
SCHEME 6. F ollow in g Step s To Obta in 2a
K2CO3, DMF, 100 °C, overnight (Hanessian’s conditions8g).
a
Isolated yields by chromatography are given into parenthesis.
SCHEME 4. N-Dep r otection Accor d in g to r ef 12a
a
Reagents and conditions: (i) TBDMSCl, imidazole, DMF, rt,
95%; (ii) NaOAc, 18-c-6, AcOH, rt, 17 h, 68% conversion; (iii) Et3N,
AcOEt, 70 °C, 5 h, 66% conversion.
a
Reagents and conditions: (i) NBS, Br2 cat., CH2Cl2, H2O, hν,
rt; (ii) pTsOH, acetone, H2O, rt; yields are 95% of 10b,12 95% of
10c,12 92% of 10d , and 82% of 10e.
This is consistent with the well-known migrating ability
of the tert-butyl group. With R ) i-Pr (10d ), an interme-
diate situation was observed: an equimolar mixture of
4-(isopropanoyloxy)-2-azetidinone 11d (H-4 at 5.84 δ) and
4-(isopropyloxycarbonyl)-2-azetidinone 12d (H-4 at 4.29
δ) was formed. Thus, azetidinyl and isopropyl (secondary
alkyl group) should similarly stabilize a positive charge
in development. Interestingly, the cyclopropyl group17
showed the same migrating ability as the phenyl group;
in this case, the desired regioisomer 11e was quantita-
tively formed (H-4 at 5.90 δ). Thus the experimental
order of migration was t-Bu > i-Pr ) azetidinyl > c-Pr )
Ph. The particular effect of the cyclopropyl group com-
pared to the other alkyl groups (t-Bu and i-Pr) could
result from (i) the electronic properties of the exocyclic
C-C bond of the cyclopropane ring (orbitals with sp2
character);18 (ii) the reduced number of C-H bonds
involved in the hyperconjugative stabilization of the δ+
charge (4 bonds in c-Pr versus 9 and 6 bonds, respec-
tively, for t-Bu and i-Pr).
The continuation of the synthesis toward acetoxyaze-
tidinone 2 from 4-(cyclopropylcarbonyloxy)-2-azetidinone
11e was rather straightforward (Scheme 6): silylation of
the alcohol and substitution of the cyclopropylester gave
2 in nearly quantitative yield. This last reaction showed
that cyclopropylcarbonyloxy is as good leaving group as
the acetoxy group. Accordingly, 13 could be engaged in
the further synthesis of carbapenems 1, instead of
intermediate 2. This possibility has been experimentally
SCHEME 5. Ba eyer -Villiger Oxid a tion P r od u cts
C-3/C-4 substituents were exclusively in a trans relation-
ship (H-3: ∼3.0 δ, dd, J ) 4.8-5.4, 2.4 Hz; H-4: ∼4.4 δ,
d, J ) 2.4 Hz).
The following deprotection step occurred readily as
previously described (Scheme 4).12 Photobromination in
aqueous medium produced the diphenylhydroxymethyl
intermediates which were stable enough to be isolated
and stored for several days at room temperature. Their
acidic hydrolysis liberated benzophenone and azetidino-
nes 10b-e.
The Baeyer-Villiger (B-V) step was attempted on the
novel compounds 10 with t-Bu, i-Pr, and c-Pr as R side
groups and compared to the case of R ) Ph. Two possible
oxidation products with m-chloroperbenzoic acid (m-
CPBA) could be formed, corresponding to oxygen inser-
tion next to the azetidinyl moiety or next to the side group
R; this led, respectively, to â-lactams 11 (desired prod-
ucts) or 12 (Scheme 5). Results (Table 2) showed a
complete inversion of regioselectivity when replacing R
) Ph (10b)8g by R ) t-Bu (10c): 4-(t-butoxycarbonyl)-2-
azetidinone 12c16 was the only oxidation product, from
1H NMR analysis of the crude mixture (H-4 at 4.18 δ).
(16) Shiozaki, M.; Ishida, N.; Hiraoka, T.; Maruyama, H. Tetrahe-
dron 1984, 40, 1795.
(17) For studies of Baeyer-Villiger oxidation or related reactions
involving a cyclopropyl substituent, see: (a) Emmons, W. D.; Lucas,
G. B. J . Am. Chem. Soc. 1955, 77, 2287. (b) Wiberg, K. B.; Snoonian,
J . R. J . Org. Chem. 1998, 63, 1390. (c) Rosenberg, M. G.; Haslinger,
U.; Brinker, U. H. J . Org. Chem. 2002, 67, 450.
(18) Smith, M. B.; March, J . March’s Advanced Organic Chemistry,
5th ed.; J ohn Wiley & Sons: New York, 2001; pp 130-131.
3196 J . Org. Chem., Vol. 69, No. 9, 2004

confirmed by reacting 13 with the Meldrum ester of
2-methylmalonic acid (14) to furnish the known azetidi-
none 15 (Scheme 6).19
pounds. Our revisited route toward intermediate 2 (or
13) should also offer a convenient access to carbacephems
and trinems.1
In revisiting Hanessian’s synthesis of acetoxyazetidi-
none 2, we synthesized 13 with 47% overall yield from
bromomethylcyclopropyl ketone 4d and with 39% overall
yield from epoxybutanoate 3. We used a novel N-
protective group, the benzhydryl group, which could be
friendly cleaved, but imposed a dramatic change of the
nature of the R substituent (initially a phenyl group). The
requirements for the cyclization step, which needs a
sterically hindered R group, and for the Baeyer-Villiger
oxidation, which needs a poor electron-donating R group,
appeared rather opposite. We found the right compromise
with the cyclopropyl group: its steric effect is comparable
to that of the tert-butyl (or i-Pr) group, but its migrating
ability in B-V rearrangement is similar to that of the
phenyl group.
Ack n ow led gm en t. We thank Tessenderlo Chemie
for financial support, Drs. Marc Belmans and Luc
Kemps for discussions, Brigitte Clamot and Anny De-
koker for technical assistance, and Dr. Roland Touillaux
for NMR analysis. J .M.-B. is senior research associate
of FNRS (Fonds National de la Recherche Scientifique),
Belgium. This work was partially supported by the PAI
program (Poˆle d’Attraction Interuniversitaire, Belgium,
2002-2006, “Protein structure and function in the post-
genomic, proteomic era-Workpackage 3: active-site
serine penicilloyl transferases”).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analyses for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The use of a cyclopropyl substituent to direct the B-V
regiochemistry was scarcely described in the literature,
and to our knowledge, not exploited as a valuable strat-
egy in the total synthesis of biologically active com-
J O030377Y
(19) J acopin, C.; Laurent, M.; Belmans, M.; Kemps, L.; Ce´re´siat,
M.; Marchand-Brynaert, J . Tetrahedron 2001, 57, 10383.
J . Org. Chem, Vol. 69, No. 9, 2004 3197