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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Org Lett. Author manuscript; available in PMC 2010 August 20.
Published in final edited form as:
PMCID: PMC2736320

A Catalytic Asymmetric Route to Carbapenems


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Efficient syntheses of N-acetyl thienamycin and epithienamycin A in readily deprotected form are reported where three contiguous stereocenters are established in a single catalytic asymmetric azetidinone-forming reaction. These examples are a template for synthesizing C5/C6 cis or trans carbapenems with independent control of the C8 stereocenter. A library of oxidatively and sterochemically defined azetidinone precursors to a variety of naturally-occurring carbapenems and potential biosynthetic intermediates has been prepared to facilitate studies of carbapenem antibiotic biosynthesis.

Thienamycin and related carbapenem antibiotics show high potency, a broad spectrum of activity and comparative stability to many clinically-encountered β-lactamases that confer resistance to penicillins and cephalosporins. Efficient, scalable routes for the preparation of carbapenems are a valuable practical goal because they are not available by large scale fermentation and/or semi-synthesis. Most carbapenem syntheses proceed through azetidinone intermediates, and the majority of the synthetic effort is expended in establishing properly functionalized stereocenters at C-5, C-6 and C-8 (Figure 1). Previous reports have shown that desired C-5 and C-6 configurations can be derived from chiral precursors.1a-d Some common methods of azetidinone formation are ester enolate-imine condensations,2a-d [2+2] cycloaddition reactions of olefins with isocyanates3 or ketenes with imines.4a-c The stereochemical outcome of the latter is highly dependent upon the substrates and reaction conditions giving C-3 and C-4 cis or trans diastereoselectively, but not enantioselectively. Optically active material has been obtained in specific cases by using ketenes or imines bearing chiral auxiliaries, but these reactions are not applicable to general carbapenem synthesis.5a-c Azetidinones with a carboxylic acid 8, carboxymethylene 9 or an equivalent group at C-4 can be converted by several methods to carbapenems. 6a-c

Figure 1
a. Naturally occurring carbapenems and potential biosynthetic intermediates. b. Azetidinone forming reactions of ketenes and imines.

To carry out biosynthetic studies of the carbapenems, we required syntheses of naturally-occurring carbapenams/ems and potential pathway intermediates to serve as enzyme substrates and reference standards. The naturally-occurring carbapenems number about 50 and constitute a native combinatorial library exhibiting modulated biological activities expressed in substituent and oxidation state variation at C-2 and C-6.7 Moreover, advanced investigations of the simplest carbapenem, carbapen-2-em-3-carboxylic acid,8 and thienamycin9 have established that an epimerization event occurs at C-5 (from S to R) during the course of biosynthesis. Thus, an approach was needed to establish either the 5S- or 5R-configuration, the relative cis or trans stereochemistry of the C-6 substituent and set the historically troublesome C-8 hydroxyl stereocenter.

Given the variety of products desired, we were limited by the scope of existing methods. We chose to build upon a recently developed catalytic, asymmetric azetidinone-forming reaction. This robust, scalable method uses the cinchona alkaloid derivatives o-benzoylquinine (BQ) or its pseudoenantiomer o-benzoylquinidine (BQd) as catalysts to give cis-substituted azetidinones with excellent enantioselectivity (ee) and diastereoselectivity (dr).10a-e We reasoned that if this system could be applied to carbapenem synthesis, catalyst choice would determine the C-5 and C-6 stereocenters and enantiopure ketenes could be employed to establish that at C-8.11,12 Various ketenes could be used to make cis azetidinones, which could be epimerized to trans, to afford precursors of cis or trans carbapenems.

We investigated the azetidinone-forming reaction of simple alkyl ketenes with imine 7 catalyzed by BQ or BQd (Table 1). Ketenes were generated from the corresponding acid chlorides by treatment with triethylamine in situ. The reaction produced cis-azetidinones with excellent enantioselectivity, and only a trace of the trans diastereomer. Propionyl chloride, butyryl chloride and isovaleryl chloride were used to synthesize azetidinone precursors of deshydroxy northienamycin 5, PS-5 (3) and PS-6 (4). To synthesize azetidinone precursors of thienamycin (1) and epithienamycin A (2), ethyl (3S)-hydroxybutanoate and ethyl (3R)-hydroxybutanoate were silated and saponified to give the corresponding acids, which were converted to the acid chlorides for ketene generation.13 The expected azetidinones were produced on a multigram scale.

Table 1
Azetidinone precursors of carbapenems

It was postulated that the chiral transition state of the azetidinone-forming reaction might be used to amplify diastereoselection at C-8 from a pool of racemic starting material. This possibility was investigated using silyl-protected 3-hydroxy butyryl chloride as the ketene precursor. The racemic 3-hydroxybutyrate was protected as the t-butyldimethyl silyl, t-butyldiphenyl silyl or triisopropyl silyl ether in anticipation that steric bulk would accentuate any stereoselection observed resulting from bias in the transition state. One equivalent of each ketene (16–18) was used under the standard reaction conditions showing only modest selectivity (ca. 2:1) when the bulky triisopropyl silyl group was used (Scheme 1). When the reaction was repeated with two and three equivalents of ketene, selectivity did not improve and yields decreased. This observation further implied that the catalyst has minimal bias for (S) or (R) 3-hydroxy butyrates and efficiently catalyzed cis-azetidinone formation with either enantiomer.

Scheme 1
Effect of C-8 stereocenter on catalysis

Having made azetidinones with absolute configurational control of three contiguous stereocenters, we synthesized p-nitrobenzyl (PNB) N-acetyl thienamycin (24) and PNB epithienamycin A (32). Initially the C-4 acids of azetidinones 13 and 14 were accessed by hydrogenolysis of the benzyl esters, but the relatively reactive N-tosyl azetidnones were not compatible with downstream reactions. We resolved to remove the tosyl group early in the synthesis. After smooth detosylation with samarium (II) diiodide14a,b the resulting ß-lactams were amenable to efficient completion of carbapenem synthesis (Scheme 2).

Scheme 2
Syntheses of protected N-acetyl thienamycin and epithienamycin A

For the preparation of 24 and C-5/C-6 trans carbapenems, the benzyl ester of 19 was removed by hydrogenolysis. The resulting acid 20 was oxidatively decarboxylated with lead tetraacetate to epimerize the C-5 stereocenter and produce a known thienamycin precursor, acetoxy azetidinone 21.15 This can be readily coupled with TBS enol 33 and desilylated to give diazo azetidinone 23. The final stages of carbapenem synthesis were achieved by cyclization of 23 to the 2-oxocarbapenam with rhodium acetate. After filtration of the rhodium catalyst, the 2-oxocarbapenam was activated as its enolphosphate, which underwent heteroconjugate addition with N-acetylcysteamine (HSNAc) to give PNB N-acetyl thienamycin (24). The PNB ester, conventionally used in carbapenem syntheses can be readily removed by hydrogenolysis to afford the natural product.16

Syntheses of 32 and C-5/C-6 cis carbapenems start with TBS protection of the azetidinone nitrogen followed by hydrogenolysis of the C-5 benzyl ester to the acid 27. In this case the Arndt-Eistert homologation was employed to introduce a methylene and preserve the cis stereochemistry. Azetidinone carboxylic acid 27 was activated as the acid chloride, and this was substituted with diazomethane to give diazoketone 28. The diazoketone was unstable to silica gel chromatography and was subjected directly to light-promoted Wolff rearrangement to give homologated acid 29.17 This intermediate was activated with carbonyldiimidazole and the final acetate unit was added by the method of Masamune.18 The silyl protecting groups were removed followed by the introduction of the diazo moiety to give 31, directly analogous to 23. Compound 31 was converted to PNB epithienamycin A (32) in the same manner as 23 was cyclized to PNB N-acetyl thienamycin (24), and similarly can be deprotected by hydrogenation.19a,b

Here we demonstrate an efficient approach to carbapenem synthesis with control of the three contiguous stereocenters C-5, C-6 and C-8. Azetidinone precursors of deshydroxy northienamycin (5), PS-5 (3) and PS-6 (4) have been produced on a multigram scale with excellent dr and ee. The ease of stereocontrolled azetidinone formation simplified syntheses of protected N-acetyl thienamycin (24) and epithienamycin A (32) as well as provided a general route to carbapenems possessing C-5/C-6 cis or trans configurations with independent control of C-8 hydroxyl stereochemistry. These efficient and flexible approaches allow access to the many naturally-occurring carbapenems and will enable investigation of their biosynthetic relationships.

Supplementary Material



We thank Professor T. Lectka, and members of his laboratory for insightful discussions and encouragement. We also acknowledge Dr. I. P. Mortimer (JHU) for performing mass spectrometric analysis and the NIH for financial support (AI014937).


Supporting Information Available: Experimental procedures and characterization for all compounds is available free of charge via the internet at


(1) (a) Iimori T, Takahashi Y, Izawa T, Kobayashi S, Ohno M. J. Am. Chem. Soc. 1983;105:1659–1660. (b) Bateson JH, Robins AM, Southgate R. J. Chem. Soc., Perkin Trans. 1991;1:29–35. (c) Melillo DG, Shinkai I, Liu T, Ryan K, Sletzinger M. Tetrahedron Lett. 1980;21:2783–2786. (d) Karady S, Amato JS, Reamer RA, Weinstock LM. J. Am. Chem. Soc. 1981;103:6765–6767.
(2) (a) Hart DJ, Ha DC. Chem. Rev. 1989;89:1447–1465. (b) Hart DJ, Lee CS, Pirkle WH, Hyon MH, Tsipouras A. J. Am. Chem. Soc. 1986;108:6054–6056. [PubMed] (c) Cainelli G, Giacomini D, Panunzio M. Tetrahedron Lett. 1985;26:937–940. (d) Georg GI, Kant J, Gill HS. J. Am. Chem. Soc. 1987;109:1129–1135.
(3) Ohashi T, Kan K, Ueyama N, Sada I, Myama A, Watanabe K. U.S. patent 4791198. 1988.
(4) (a) Brandi A, Cicchi S, Cordero FM. Chem. Rev. 2008;108:3988–4035. [PubMed] (b) Fu N, Tidwell TT. Tetrahedron. 2008;64:10465–10496. (c) Palomo Claudio, Palomo JMA, Ganboa Inaki, Oiarbide Mikel. Eur. J. Org. Chem. 1999:3223–3235.
(5) (a) Sunagawa M, Matsumura H, Enomoto M, Inoue T, Sasaki A. Chem. Pharm. Bull. 1991;39:1931–1938. (b) Sasaki A, Goda K, Enomoto M, Sunagawa M. Chem. Pharm. Bull. 1992;40:1094–1097. [PubMed] (c) Colombo M, Crugnola A, Franceshi G, Lombardi P. U.K. Patent Appl. GB 2144419. 1985.
(6) (a) Shih DH, Baker F, Cama L, Christensen BG. Heterocycles. 1984;21:29–40. (b) Reider PJ, Grabowski EJJ. Tetrahedron Lett. 1982;23:2293–2296. (c) Devries JG, Hauser G, Sigmund G. Tetrahedron Lett. 1984;25:5989–5992.
(7) Fischbach MA, Clardy J. Nat. Chem. Biol. 2007;3:353–355. [PubMed]
(8) Li RF, Stapon A, Blanchfield JT, Townsend CA. J. Am. Chem. Soc. 2000;122:9296–9297.
(9) Hamed RB, Batchelar ET, Mecinovic J, Claridge TDW, Schofield CJ. ChemBioChem. 2009;10:246–250. [PubMed]
(10) (a) Taggi AE, Hafez AM, Wack H, Young B, Ferraris D, Lectka T. J. Am. Chem. Soc. 2002;124:6626–6635. [PubMed] (b) France S, Wack H, Hafez AM, Taggi AE, Witsil DR, Lectka T. Org. Lett. 2002;4:1603–1605. [PubMed] (c) France S, Shah MH, Weatherwax A, Wack H, Roth JP, Lectka T. J. Am. Chem. Soc. 2005;127:1206–1215. [PubMed] (d) France S, Weatherwax A, Taggi AE, Lectka T. Acc. Chem. Res. 2004;37:592–600. [PubMed] (e) Shah MH, France S, Lectka T. Synlett. 2003:1937–1939.
(11) Georg GI, Kant J, Gill HS. J. Am. Chem. Soc. 1987;109:1129–1135.
(12) Cainelli G, Contento M, Giacomini D, Panunzio M. Tetrahedron Lett. 1985;26:937–940.
(13) Lengweiler UD, Fritz MG, Seebach D. Helv. Chim. Acta. 1996;79:670–701.
(14) (a) Vedejs E, Lin SZ. J. Org. Chem. 1994;59:1602–1603. (b) Hasegawa E, Curran DP. J. Org. Chem. 1993;58:5008–5010.
(15) Berks HA. Tetrahedron. 1996;53(2):331–375.
(16) Corbett DF, Coulton S, Southgate R. J. Chem. Soc., Perkin Trans. 1982;1:3011–3016.
(17) Fetter J, Lempert K, Gizur T, Nyitrai J, Kajtanperedy M, Simig G, Hornyak G, Doleschall G. J. Chem. Soc., Perkin Trans. 1986;1:221–227.
(18) Brooks DW, Lu LDL, Masamune S. Angew. Chem., Int. Ed. 1979;18:72–74.
(19) (a) Kametani T, Huang SP, Nagahara T, Ihara M. J. Chem. Soc., Perkin Trans. 1981;1:2282–2286. (b) Kametani T, Nagahara T, Ihara M. J. Chem. Soc., Perkin Trans. 1981;1:3048–3052.