A Comprehensive Review on C-3 Functionalization of β-Lactams

Author(s): Reshma Nagpal, Jitender Bhalla*, Shamsher S. Bari.

Journal Name: Current Organic Synthesis

Volume 16 , Issue 1 , 2019

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Graphical Abstract:


Background: A lot of advancement has been made in the area of β-lactams in recent times. Most of the research is targeted towards the synthesis of novel β-lactams, their functionalization and exploring their biological potential. The C-3 functionalization of β-lactams has continued to attract considerable interest of the scientific community due to their utility as versatile intermediates in organic synthesis and their therapeutic applications. This has led to the significant increase in efforts towards developing efficient and economic strategies for C-3 functionalized β-lactams.

Objective: The present review aims to highlight recent advancement made in C-3 functionalization of β - lactams.

Conclusion: To summarize, functionalization of β-lactams at C-3 is an essential aspect of β-lactam chemistry in order to improve/modify its synthetic utility as well as biological potential. The C-3 carbocation equivalent method has emerged as an important and convenient strategy for C-3 functionalization of β-lactam heterocycles which provides a wide range of β-lactams viz. 3-alkylated β-lactams, 3-aryl/heteroarylated β-lactams, 3- alkoxylated β-lactams. On the other hand, base mediated functionalization of β-lactams via carbanion intermediate is another useful approach but their scope is limited by the requirement of stringent reaction conditions. In addition to this, organometallic reagent mediated α-alkylation of 3-halo/3-keto-β-lactams also emerged as interesting methods for the synthesis of functionalized β-lactams having good yields and diastereoselectivities.

Keywords: C-3 functionalization, β-lactam, C-3 carbocation, C-3 carbanion, α-allylation, grignard reagent.

Arya, N.; Jagdale, A.Y.; Patil, T.A.; Yeramwar, S.S.; Holikatti, S.S.; Dwivedi, J.; Shishoo, C.J.; Jain, K.S. The chemistry and biological potential of azetidin-2-ones. Eur. J. Med. Chem., 2014, 74, 619-656.
Sandanayaka, V.P.; Parshad, A.S. Resistance to beta-lactam antibiotics: structure and mechanism based design of beta-lactamase inhibitors. Curr. Med. Chem., 2002, 9, 1145-1165. [and reference cited therein].
Bhalla, A.; Bari, S.S.; Bhalla, J. Synthesis of diverse β-lactams: Role of appended hetero moiety on its activity In: Beta-Lactams: Novel SyntheticPathways And Applications; Banik, B., Ed.; Springer International Publishing AG, Germany, 2017; pp. 1-40. (and reference cited therein)
Ojima, I.; Delaloge, F. Asymmetric synthesis of building-blocks for peptides and peptidomimetics by means of the β-lactam synthon method. Chem. Soc. Rev., 1997, 26, 377-386.
Ojima, I. Asymmetric synthesis of building-blocks for peptides and peptidomimetics by means of the β-lactam synthon method. Acc. Chem. Res., 1995, 28, 383-389.
Suffness, M. Taxol Science and Applications; CRC Press: Boca Raton, FL, 1995.
Rosenblum, S.B.; Huynh, T.; Afonso, A.; Davis, H.R., Jr; Yumibe, N.; Clader, J.W.; Burnett, D.A. Discovery of 1-(4-Fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption. J. Med. Chem., 1998, 41, 973-980.
Hanessian, S.; Alpegiani, M. Highly stereoselective free radical C-6-allylation of penams- synthesis of a noval β-lactamase inhibitor. Tetrahedron, 1989, 45, 941-950.
Firestone, R.A.; Barker, P.L.; Pisano, J.M.; Ashe, B.M.; Dahlgren, M.E. Monocyclic β-lactam inhibitors of human leukocyte elastase. Tetrahedron, 1990, 46, 2255-2262.
Singh, G.S.; Sudheesh, S. Advances in synthesis of monocyclic β-lactams. Arkivoc, 2014, (i), 337-385.
Orbegozo, T.; Burel, F.; Jubault, P.; Pannecoucke, X. 3,3-gem-difluorinated-β-lactams:synthesis pathways and applications. Tetrahedron, 2013, 69, 4015-4039.
Bhattacharya, B.; Turos, E. Synthesis and biology of N-thiolated β-lactams. Tetrahedron, 2012, 68, 10665-10685.
Stecko, S.; Furman, B.; Chemielewski, M. Kinugasa reaction: an ugly duckling of β-lactam chemistry. Tetrahedron, 2014, 70, 7817-7844.
Fu, N.; Tidwell, T.T. Preparation of β-lactams by [2+2] cycloaddition of ketenes and imines. Tetrahedron, 2008, 64, 10465-10496.
Vessally, E.; Babazadeh, M.; Hosseinian, A.; Edjlali, L.; Sreerama, L. Recent advances in synthesis of functionalized β-lactams through cyclization of N-propargyl amine/amide derivatives. Curr. Org. Chem., 2018, 22, 199-205.
Bose, A.K.; Krishnan, L.; Wagle, D.R.; Manhas, M.S. A novel chemical transformation of 3-vinyl-4-substituted-2-azetidinones. Tetrahedron Lett., 1986, 27, 5955-5958.
McCarney, C.C.; Ward, R.S. An improved method for the preparation of monoalkylketens. J. Chem. Soc., Perkin Trans. I., 1975, 1600-1603.
Sauer, J.C. Ketene dimers from acid halides. J. Am. Chem. Soc., 1947, 69, 2444-2448.
Palomo, C.; Cossio, F.P.; Odriozola, J.M.; Oiarbide, M.; Ontoria, J.M. Alkyl(phenylthio)ketenes as synthetic equivalents of monoalkylketenes: A concise general route to 3-alkyl β-lactams as carbapenem building-blocks. Tetrahedron Lett., 1989, 30, 4577-4580.
Palomo, C.; Cossio, F.P.; Odiozola, J.M.; Oiarbide, M.; Ontoria, J.M. Preparation of 3-alkyl. beta.-lactams via the ketene imine cycloaddition reaction using. alpha.-(phenylthio)alkanoyl halides as starting materials: application to the synthesis of (.+-.)-carbapenem building blocks and related compounds. J. Org. Chem., 1991, 56, 4418-4428.
Palomo, C.; Aizpurua, J.M.; Lopez, M.C.; Aurrekoetxea, N.; Oiarbide, M. Addition of α-bromoesters to azetidine-2,3-diones promoted by zinc-trimethylchlorosilane: a general synthesis of 3-trimethyisilyloxyazetidin-2-ones and α-alkylidene β-lactams. Tetrahedron Lett., 1990, 31, 6425-6428.
Bojilova, A.; Rodios, N.A. Synthesis and spectroscopic characterization of 1- [1,2,3-triazol1-yl]-4-aroylazetidin-2-ones. J. Heterocycl. Chem., 1991, 28, 593-598.
Teng, M.; Miller, M.J. Diastereoselective addition of nucleophiles to the C3 position of N-(tosyloxy)-.beta.-lactams. J. Am. Chem. Soc., 1993, 115, 548-554.
Burnett, D.A.; Caplen, M.A.; Davis, Jr , H.R.; Burrier, R.E.; Clader, J.W. 2-Azetidinones as inhibitors of cholesterol absorption. J. Med. Chem., 1994, 37, 1733-1736.
Bellettini, J.R.; Miller, M.J. Intermolecular addition of amines to an N-tosyloxy β-lactam. J. Org. Chem., 1996, 61, 7959-7962.
Jayaraman, M.; Manhas, M.S.; Bose, A.K. Environ-friendly approaches to densely functionalized β-lactams. Tetrahedron Lett., 1997, 38, 709-712.
Paquette, L.A.; Rothhaar, R.R.; Isaac, M.; Rogers, L.M.; Rogers, R.D. Diastereo- and enantio- differentiation in indium-promoted allylations of 2,3-azetidinediones in water. Definition of long-range stereocontrol elements on π-facial selectivity for β-lactam synthesis. J. Org. Chem., 1998, 63, 5463-5472.
Madan, S.; Arora, R.; Venugopalan, P.; Bari, S.S. A new synthetic approach for novel C-3 substituted β-lactams. Tetrahedron Lett., 2000, 41, 5577-5581.
Bari, S.S.; Venugopalan, P.; Arora, R. A facile lewis acid-promoted allylation of azetidin-2-ones. Tetrahedron Lett., 2003, 44, 895-897.
Bhalla, A.; Madan, S.; Venugopalan, P.; Bari, S.S. C-3 β-lactam carbocation equivalents: versatile synthons for C-3 substituted β-lactams. Tetrahedron, 2006, 62, 5054-5063.
Troisi, L.; Ronzini, L.; Granito, C.; De Vitis, L.; Pindinelli, E. Stereoselective synthesis and functionalization of 4-heterosubstituted β-lactams. Tetrahedron, 2006, 62, 1564-1574.
Bhalla, A.; Venugopalan, P.; Bari, S.S. Facile stereoselective synthesis of cis- and trans-3-alkoxyazetidin-2-ones. Tetrahedron, 2006, 62, 8291-8302.
Bhalla, A.; Venugopalan, P.; Bari, S.S. A new synthetic approach to novel spiro-β-lactams. Eur. J. Org. Chem., 2006, 4943-4950.
Cheng, L.Q.; Cheng, Y. Reaction of β-lactam carbenes with alkyl isonitriles for a ready approach to 4-cyano and 4-carbamoyl substituted β-lactams. Tetrahedron, 2007, 63, 9359-9364.
Bhalla, A.; Venugopalan, P.; Bhasin, K.K.; Bari, S.S. Seleno-β-lactams: synthesis of monocyclic and spirocyclic selenoazetidin-2-ones. Tetrahedron, 2007, 63, 3195-3204.
Troisi, L.; Granito, C.; Pindinelli, E. Stereoselective synthesis and functionalization of N-alkyl-β-lactams. Tetrahedron, 2008, 64, 11632-11640.
Liang, Y.; Raju, R.; Le, T.; Taylor, C.D.; Howell, A.R. Cross-metathesis of α-methylene-β-lactams: the first tetrasubstituted alkenes by CM. Tetrahedron Lett., 2009, 50, 1020-1022.
Bari, S.S. Reshma; Bhalla, A.; Hundal, G. Stereoselective synthesis and Lewis acid mediated functionalization of novel 3-methylthio-β-lactams. Tetrahedron, 2009, 65, 10060-10068.
Bari, S.S.; Arora, R.; Bhalla, A.; Venugopalan, P. Facile synthesis of (Z)- and (E)-3-allylidene-β-lactams via thermal β-elimination of trans-3-allyl-3-sulfinyl-β-lactams. Tetrahedron Lett., 2010, 51, 1719-1722.
Tarui, A.; Kondo, S.; Sato, K.; Omote, M.; Minami, H.; Miwa, Y.; Ando, A. Ni-catalyzed α-arylation of secondary α-bromo-α-fluoro-β-lactam: cross-coupling of a secondary fluorine-containing electrophile. Tetrahedron, 2013, 69, 1559-1565.
Decamps, S.; Sevaille, L.; Ongeri, S.; Crousse, B. Access to novel functionalized trifluoromethyl β-lactams by ring expansion of aziridines. Org. Biomol. Chem., 2014, 12, 6345-6348.
Tarui, A.; Tanaka, A.; Ueo, M.; Sato, K.; Omote, M.; Ando, A. Synthesis of a fluorinated Ezetimibe analogue using radical allylation of α-bromo-α-fluoro-β-lactam. New J. Chem., 2015, 39, 9325-9329.
Bhalla, A.; Bari, S.S.; Bhalla, J.; Khullar, S.; Mandal, S. Facile synthesis of novel halogenated 4-pyrazolylspirocyclic-β-lactams: versatile heterocyclic synthons. Tetrahedron Lett., 2016, 57, 2822-2828.
Bhalla, A.; Bari, S.S.; Vats, S.; Bhalla, J.; Sharma, K.; Narula, D. One pot, simple, and efficient synthesis of (E)- and (Z)-3-allylidene-β-lactams from 3-allyl-3-phenylseleno-β-lactams: analogues of β-lactamase inhibitors. Tetrahedron Lett., 2016, 57, 4763-4766.
Bhalla, A.; Modi, G.; Bari, S.S.; Kumari, A.; Berry, S.; Hundal, G. Stereoselective synthesis of novel C-3 functionalized 3-sulfonyl-β-lactams: Promising biologically active heterocyclic scaffolds. Tetrahedron Lett., 2017, 58, 1160-1165.
Bhalla, J.; Bari, S.S.; Rathee, A.; Kumar, A.; Bhalla, A. Pyrimidine and pyrazole linked azetidin-2-ones: Entry to novel class of β-lactam heterocycles. J. Heterocycl. Chem., 2017, 54, 2297-2306.

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Year: 2019
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DOI: 10.2174/1570179415666181116103341
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