View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by ePrints@Bangalore University REVIEW ▌1569 Propanephosphonicreview Acid Anhydride (T3P®) - A Benign Reagent for Diverse Applications Inclusive of Large-Scale Synthesis PropanephosphonicBasavaprabhu, Acid Anhydride T. M. Vishwanatha, Nageswara Rao Panguluri, Vommina V. Sureshbabu* #109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560 001, India Fax +91(80)22292848; E-mail: [email protected]; E-mail: [email protected]; E-mail: [email protected] Received: 12.02.2013; Accepted after revision: 26.03.2013 been developed and yet there is a constant impetus for the Abstract: Propanephosphonic acid anhydride (T3P®) is a prevail- ing coupling and dehydrating agent with many desirable properties development of newer condensation agents, which in re- which render it a reagent of choice for a plethora of reactions and, cent days is guided by the requirements for the synthesis befittingly, its application in organic synthesis is rapidly increasing. of biologically important molecules. Each coupling re- Since its introduction as a peptide coupling agent in 1980, the realm agent has tunable structure, unique reactivity and distinct of applications of T3P has expanded. Currently its use is found in a chemical as well as physical properties. Hence, utility of broad range of reactions, including condensation, functional group these reagents has moved far beyond their use as simple transformation, heterocycles preparation, rearrangements, and ca- coupling agents and they have been implemented for new- talysis. It offers several advantages over traditional reagents, such as high yield, chemical and optical purity, broad functional group er applications such as the use in synthesis of aldehydes, tolerance and easy work-up. The reagent is attractive for large-scale alcohols, acetylenes, heterocycles and several other useful synthesis as well, and particularly so for multi-kilogram scale prep- intermediates. arations of drug molecules. This article reviews the hitherto report- Carbodiimides, as well as onium, uronium and guanidini- ed applications of T3P as a reagent in organic synthesis. Focus is also placed on the use of T3P for large-scale synthesis. um salts, lead the directory of diverse classes of coupling agents developed. Among them, a large variety of phos- 1 Introduction phorus-based reagents have been found to be attractive 2 Structure and Preparation since they render the reactions clean and high-yielding in 3 T3P in Peptide Chemistry small-scale as well as large-scale preparations. Newer 3.1 As a Coupling Agent phosphorus-based reagents that are relevant in the context of green synthesis are constantly being explored. Among 3.2 Synthesis of Amino Acid Derivatives and Peptidomimetics the wide array of phosphorus-based reagents available, di- 4 General Applications phenylphosphorazidate (DPPA; 1), diethyl-2-(3-oxo-2,3- 4.1 As a Carboxylic Acid Activator dihydro-1,2-benzisosulfonazolyl)phosphonate (DEBP; 4.2 As a Dehydrating Agent 2), N,N′-bismorpholinophosphonic chloride 3 (BMPCl), 4.3 Synthesis of Heterocycles 1-oxo-chlorophospholane (CptCl; 4), 3-(diethoxyphos- phoryloxy)-1,2,3-benzotriazin-4(3H)-one diethyl tartar- 4.4 Oxidation Reactions ate (DEPBT; 5), phosphoric acid 3,5-dioxo-10-oxa-4- 4.5 Carbon–Carbon Bond Formation azatricyclo[5.2.1.0]dec-8-en-4-yl ester diphenyl ester 4.6 Rearrangement Reactions (ENDPP; 6a), norborn-5-ene-2,3-dicarboximidodiphe- 4.7 Synthesis of Drugs on Laboratory and Large Scales nylphosphate (NDPP; 6b), bis(2-oxooxazolidin-3- 5 Recent Applications yl)phosphinic chloride (BopCl; 7) have been used widely in organic synthesis and peptide chemistry in particular Downloaded by: National University of Singapore. Copyrighted material. 6 Conclusion (Figure 1). Key words: coupling, racemization, rearrangement, large-scale synthesis n-Propanephosphonic acid anhydride, popularly known as T3P® (8; Figure 2), is one such phosphorus-containing reagent among the many discovered in recent years. It is a phosphorus-based cyclic anhydride introduced by 1 Introduction Wissmann et al. in 1980.1 It has also been identified by other names, including 1,3,5,2,4,6-trioxatriphosphori- One of the central focuses and often the one which is the nane, 2,4,6-tripropyl-2,4,6-trioxide, n-propylphosphonic key to the success of organic synthesis is the kind of re- cyclic anhydride (PPACA) and propane phosphonic acid agents and conditions used to synthesize molecules in an anhydride (PPAA) but will be referred to throughout this efficient manner. In the endeavor of discovering new re- review as simply T3P. It was initially employed as peptide agents, numerous coupling and dehydrating agents have coupling agent and thereafter its utility had been success- fully demonstrated in a series of conversions, as well as in SYNTHESIS 2013, 45, 1569–1601 industrial applications as a reagent for large-scale synthe- Advanced online publication: 03.06.20130039-78811437-210X sis of natural products, heterocycles and drugs. A phe- DOI: 10.1055/s-0033-1338989; Art ID: SS-2013-E0121-R nomenal expansion in its applications has been witnessed © Georg Thieme Verlag Stuttgart · New York 1570 Basavaprabhu et al. REVIEW Biographical Sketches█ Basavaprabhu was born in 2008. Presently he is pursu- ment of Chemistry, Central Raichur, Karnataka, India. ing research in peptides and College Campus, Bangalore He completed his M.Sc. in peptidomimetics under the University. organic chemistry from supervision of Prof. V. V. Bangalore University in Sureshbabu at the Depart- T. M. Vishwanatha was from Bangalore University. lore University. His Ph.D. born in 1984 in Chikkamag- In 2007, he joined Prof. V. research focuses on the de- alur, Karnataka, India. He V. Sureshababu’s group at sign and synthesis of novel received his B.Sc. and the Department of Chemis- class of peptidomimetics. M.Sc. (organic chemistry) try, Central College, Banga- Nageswara Rao Panguluri & Science, Nagarjuna Uni- Sureshbabu at the Depart- was born in Guntur, Andhra versity, Guntur in 2008. ment of Chemistry, Central Pradesh, India in 1985. He Presently he is pursuing re- College Campus, Bangalore completed an M.Sc. in or- search in peptides and pepti- University. ganic chemistry from P. B. domimetics under the Siddhartha College of Arts supervision of Prof. V. V. Professor Vommina V. 1989, he was appointed as ment of new reagents for Sureshbabu was born in Lecturer at the same depart- efficient peptide synthesis, Nellore, Andhra Pradesh, ment. Later, he took up a design and synthesis of pep- India in 1961. He obtained postdoctoral assignment at tidomimetics, incorporation an M.Sc. in chemistry from CUNY, New York (USA) of unnatural linkages into Sri Krishnadevaraya Uni- where he worked on the peptide backbones, native versity, Ananthapur, India synthesis of GPCR frag- chemical ligation, C-termi- Downloaded by: National University of Singapore. Copyrighted material. in 1983. He was invited by ments through native chem- nal versus N-terminal Prof. K. M. Sivanandaiah to ical ligation. At present, he modifications for peptido- pursue a Ph.D. degree at is working as a Professor at mimetic synthesis, and utili- Central College, Bangalore the Department of Studies in ty of the Fmoc group in working in the area of pep- Chemistry, Central College, solution-phase synthesis. tide chemistry. After the Bangalore. His research in- completion of his Ph.D. in terests include the develop- Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1571 philes. T3P is a clear, colorless syrup with a boiling point O O of 280 °C/0.1 mbar. O Cl P N O O EtO P N N PhO P P N3 EtO PhO S O Cl O2 O O O O O O H O, reflux distillation DPPA (1) DEBP (2) BMPCl (3) CptCl (4) 2 P P P P OH P Cl HO O O OH Ac O 2 OH Cl HCl OEt 10 11 O O EtO P O 9 O O N O intramolecular O P condensation reactive N PhO Cl heat distillation P O N X N N PhO N O O O O P DEPBT (5)ENDPP (6a; X = O) BopCl (7) O O NDPP (6b; X = CH ) 2 P P O O O Figure 1 Structures of widely used phosphorus-containing coupling 8 reagents Scheme 1 Preparation of T3P owing to its coupling, dehydrating and catalytic proper- ties, which can be harnessed under very mild conditions. Significantly, T3P has been shown to be more promising The original protocols for the synthesis of T3P used n- for large-scale preparations because of its low toxicity, propyl phosphoric acid (11) or n-propyl phosphoric di- 2 low allergenic potential, and non-inflammability. In addi- chloride (10) as starting compounds. Wehner et al. em- tion, the solubility of its remnants in water renders the ployed 10 as a precursor, which was initially heated at easy handling of the reagent on large scale as well. On the 40 °C and then raised to 80 °C. After complete addition of other hand, safety parameters for the highly sensitizing water, followed by heating the reaction mixture in a con- carbodiimide reagents, or for the preparation, storage and trolled manner at 80 °C/17 torr for three hours and then at handling of explosion-prone benzotriazole derivatives, re- 80 °C/5 torr for another three hours, oligomeric unit 9 re- quire specific attention. sulted, with the liberation of gaseous hydrochloric acid. The oligomeric acid, on distillation at 200 °C under re- duced pressure (0.2 mbar), afforded the trimeric anhy- dride 8 in respectable yield. Alternatively, a two-step O O 1 O P P synthesis of T3P was developed by Wissmann et al. O O P (Scheme 1) in which 11 was heated at reflux with acetic O anhydride followed by removal of excess acetic anhydride T3P (8) and acetic acid by vacuum distillation at 100 mbar under an inert atmosphere.