Regioselective Baeyer-Villiger Oxidation in 4-Carbonyl-2-azetidinone Series: A Revisited Route toward Carbapenem Precursor
SCHEME 1. General Retrosynthesis of the Carbapenem Family
Mathieu Laurent,† Marcel Ce´re´siat,‡ and Jacqueline Marchand-Brynaert*,† Unite´ de Chimie organique et me´ dicinale, Universite´ catholique de Louvain, Baˆ timent Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium, and Tessenderlo Chemie s.a./n.v., Rue du Troˆ ne 130, B-1050 Bruxelles, Belgium
[email protected] Received December 10, 2003
Abstract: 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.
Carbapenems 1 form a growing class of β-lactam antibiotics1 that occupies a central role in the fight against bacteria resistant to β-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 β-lactamases.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 rearrangement,8 and others.9 * Corresponding author: Tel: + 32-10-472740. Fax: + 32-10-474168. † Universite ´ catholique de Louvain. ‡ Tessenderlo Chemie. (1) (a) The Chemistry of β-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 Antibacterial Agents; ASM Press: Washington, DC, 2003. (c) Walsh, C. Antibiotics: Actions, Origins, Resistance; ASM Press: Washington, DC, 2003. (3) For reviews on β-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.
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 rearrangements, 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-azetidinones8d-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 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 Lett. 1988, 29, 815. (d) Georg, G. I.; Kant, J.; Gill, H. S. J. Am. Chem. Soc. 1987, 109, 1129. (6) (a) Okita, M.; Wakamatsu, T.; Ban, Y. J. C. S. Chem. Commun. 1979, 749. (b) Mori, M.; Kagechika, K.; Tohjima, K.; Shibasaki, M. 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.; Kumobayashi, 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-methylcarbonylazetidinones, 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-phenylcarbonylazetidinones, see: (d) Altamura, M.; Ricci, M. Synth. Commun. 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-formylazetidinones, 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. (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.; John 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.; John 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. 10.1021/jo030377y CCC: $27.50 © 2004 American Chemical Society
3194
J. Org. Chem. 2004, 69, 3194-3197
Published on Web 03/26/2004
Synthesis of Precursorsa
the question of migrating ability of the azetidinyl group versus secondary and tertiary alkyl groups. The Hanessian’s strategy was based on the C-3/C-4 ring closure for the formation of the β-lactam ring from (2R,3R)-epoxybutyramide precursors (Scheme 2). In these intermediates, 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 bromination 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
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 remained 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? This paper discloses our original solution to those questions and thus proposes a synthesis of the carbapenems precursor 2 which could be possibly developed on a large scale. 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 synthesized 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 all the 1H 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 conditions 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 conditions (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. Azetidinones 7b-e were isolated by column chromatography 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. Tetrahedron 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.
SCHEME 2.
a Reagents and conditions: (i) 4a, benzhydrylbromide, neat, 70 °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. Cyclization Step with O- and C-Alkylation Products
J. Org. Chem, Vol. 69, No. 9, 2004 3195
TABLE 1. Ratio (%) of Cyclization Products
TABLE 2. Ratio (%) of B-V Products Determined by 1H
Determined by 1H NMR on the Crude Mixtures
NMR on the Crude Mixtures
R
7
8
9
R
11
12
Ph t-Bu i-Pr c-Pr H
57 100 (64) 85 (58) 92 (82) 2 (0) 0
23 0 15 8 (7) 98 (84) 74 (45)a
20 0 0 0 0 26 (13)a
Ph8d-g t-Bu i-Pr c-Pr
100 0 52 100
0 100 48 0
a
K2CO3, DMF, 100 °C, overnight (Hanessian’s conditions8g). Isolated yields by chromatography are given into parenthesis.
SCHEME 6. Following Steps To Obtain 2a
SCHEME 4. N-Deprotection According to ref 12a
a Reagents and conditions: (i) NBS, Br cat., CH Cl , H O, hν, 2 2 2 2 rt; (ii) pTsOH, acetone, H2O, rt; yields are 95% of 10b,12 95% of 10c,12 92% of 10d, and 82% of 10e.
SCHEME 5.
Baeyer-Villiger Oxidation Products
C-3/C-4 substituents were exclusively in a trans relationship (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 azetidinones 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 (mCPBA) could be formed, corresponding to oxygen insertion next to the azetidinyl moiety or next to the side group R; this led, respectively, to β-lactams 11 (desired products) 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)-2azetidinone 12c16 was the only oxidation product, from 1 H NMR analysis of the crude mixture (H-4 at 4.18 δ). 3196 J. Org. Chem., Vol. 69, No. 9, 2004
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.
This is consistent with the well-known migrating ability of the tert-butyl group. With R ) i-Pr (10d), an intermediate 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 quantitatively 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 compared 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, respectively, for t-Bu and i-Pr). The continuation of the synthesis toward acetoxyazetidinone 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 (16) Shiozaki, M.; Ishida, N.; Hiraoka, T.; Maruyama, H. Tetrahedron 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.; John Wiley & Sons: New York, 2001; pp 130-131.
confirmed by reacting 13 with the Meldrum ester of 2-methylmalonic acid (14) to furnish the known azetidinone 15 (Scheme 6).19 In revisiting Hanessian’s synthesis of acetoxyazetidinone 2, we synthesized 13 with 47% overall yield from bromomethylcyclopropyl ketone 4d and with 39% overall yield from epoxybutanoate 3. We used a novel Nprotective 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. 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 strategy in the total synthesis of biologically active com-
pounds. Our revisited route toward intermediate 2 (or 13) should also offer a convenient access to carbacephems and trinems.1
Acknowledgment. We thank Tessenderlo Chemie for financial support, Drs. Marc Belmans and Luc Kemps for discussions, Brigitte Clamot and Anny Dekoker 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 postgenomic, proteomic era-Workpackage 3: active-site serine penicilloyl transferases”). Supporting Information Available: Experimental procedures and analyses for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. JO030377Y (19) Jacopin, 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
