Propanephosphonic Acid Anhydride (T3P®)

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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 successfully 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 properties, 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 anhydride 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. The anhydride 9 thus formed was Figure 2 Structure of T3P (8) then subjected to reactive distillation at 280 °C under re- duced pressure (0.1 mbar) to yield the cyclic trimer 8 in This need for this review article is driven by the currently 77% yield. growing number of applications of T3P as a reagent of [Handling and storage: Since the anhydride form of T3P choice in organic synthesis and attempts to review the de- is sensitive to water, T3P after distillation should be dis- velopments in this regard. In addition, the practical as- solved in an anhydrous organic solvent. T3P is commer- Downloaded by: National University of Singapore. Copyrighted material. pects of the usage of the reagent are briefly emphasized. cially available as 50% (w/w) solution in a variety of solvents including ethyl acetate, dichloromethane, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, n-butyl 2 Structure and Preparation acetate and polyethylene glycol ethers and other polar, aprotic organic solvents in various ratios. A 50% solution T3P is a six-membered cyclic anhydride with phosphorus in dichloromethane can be stored in a brown bottle for and oxygen atoms alternately linked to each other. It is ob- several months. The reagent should be used under a fume tained by cyclization of trimer 9 (Scheme 1). Owing to the hood since it can cause etching. It has low toxicity and low facile nature of the –P–O–P– bonds of the ring, T3P ex- allergenic potential compared to other commonly used re- hibits increased reactivity towards a wide range of nucleo- agents such as p-toluenesulfonyl chloride or dicyclohex- ylcarbodiimide (DCC)].

3 T3P in Peptide Chemistry (78%), Boc-Tyr(tBu)-Met-Gly-OEt (84%) and a pentapeptide, Cbz-Ala-Tyr(tBu)-Gly-Val-Tyr(tBu)-OMe (93%) were also synthesized. 3.1 As a Coupling Agent

The first application of T3P was as a reagent for peptide T3P 1 R1 synthesis. The usage of coupling reagents in many cases R1 O base O O O is advantageous when compared with pre-activated acids PgHN O O O O H-base PgHN P P P O since it avoids an additional step for converting the acids O into their more reactive derivatives. In this line, several 12 15 newer coupling reagents have been developed for direct formation of peptide esters, including benzotriazol-1- R2 yloxy)tris(dimethylamino)phosphonium hexafluorophos- H2N COOMe R1 13 H phate (BOP), chlorotri(pyrrolidino)phosphoniumhexa- N COOMe fluorophosphate (PyCloP), bromotri(pyrrolidino)phos- PgHN O R2 phonium hexafluorophosphate (PyBroP), benzotriazol-1- O O O HO O O OH yloxytri(pyrrolidino)phosphonium hexafluorophosphate P P P (PyBOP), 1-[(1-(cyano-2-ethoxy-2-oxoethylideneamino- 14 oxy)dimethylaminomorpholinomethylene)]methanamini- um hexafluorophosphate (COMU), N-[(1H-benzotriazol- 9

1-yl)-(dimethylamino)methylene]-N-methylmethanamin- Pg = Boc or Cbz ium hexafluorophosphate N-oxide (HBTU), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]- Scheme 3 Formation of a peptide bond, mediated by T3P N-methylmethanaminium hexafluorophosphate N-oxide (HATU), and 1-(1-pyrrolidinyl-1H-1,2,3-triazolo[4,5- Peptide synthesis mediated by carbodiimides is generally b]pyridin-1-ylmethylene)pyrrolidinium hexafluorophos- accompanied by racemization. Different coupling re- phate N-oxide (HAPyU).3 T3P allows easy access to pep- agents show different degrees of racemization in the same tides with minimal racemization and without the necessity peptide coupling reaction. However, DCC and 1-ethyl-3- of an additive (generally used to lower the extent of race- (3-dimethylaminopropyl)carbodiimide (EDC), when used mization during carboxyl activation). When T3P was em- in combination with additives like 1-hydroxybenzotri- ployed in the condensation reaction of N-protected amino azole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl- acids 12 and 13 to form peptides 14 (Scheme 2), satisfac- HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl 1- tory yields with low ratee of racemization were observed.4 hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), 1-hydroxy-2-pyridinone (HOPy), ethyl 2-cyano-2-(hy-

2 1 R1 R T3P in EtOAc R O droxyimino)acetate (Oxyma), N-hydroxy-5-norbornene- H 3 Et3N N OH OR 3 2,3-dicarboximide (HONB), N-hydroxysuccinimide PgHN + H2N PgHN OR 0 °C to r.t. O O O R2 (HOSu) and more recently 3-hydroxy-4-oxo-3,4-dihydro- 1,2,3-benzotriazine (HODhbt) and its aza derivative, and 12 13 14 copper(I) iodide, minimize racemization to a significant Pg = Cbz, R1 = H, R2 = H, R3 = Et (80%) 1 2 t 3 extent. In contrast, T3P causes a very limited level of ra- Pg = Cbz, R = indolyl, R = CH2O Bu, R = Me (96%) Pg = Cbz, R1 = Bn, R2 = H, R3 = Et (86%) cemization without the use of any additive. 1 2 3 Pg = Boc, R = CH2CH2SMe, R = H, R = Et (94%) 1 2 3 Pg = Boc, R = indolyl, R = CH2CH2SMe, R = Me (93%) Couplings involving N-methyl amino acids and α,α-di-

α substituted amino acids is challenging because of steric Scheme 2 Synthesis of N -protected peptide esters employing T3P Downloaded by: National University of Singapore. Copyrighted material. factors. Even in such couplings, however, T3P affords the desired peptides in excellent yields (Scheme 4).2d The A major advantage of T3P lies in the fact that the other coupling was carried out in the presence of diisopropyle- products of the coupling reaction are soluble in water and thylamine or triethylamine at 0 °C within one hour. Also, do not offer any difficulty in the workup. T3P possesses in the coupling of hydroxy acid 25, excellent yield was re- good solubility in common organic solvents and its rem- ported (Scheme 5).2d nants are highly soluble in aqueous solution, thus their complete removal can be achieved by simple aqueous The preparation of the hematoregulatory nonapeptide washes. During the peptide synthesis, the cyclic anhy- [Glp-Glu(OBn)-Asp(OBn)]2-DAS-[Lys(OBn)]2 (30) was 5 dride opens up to yield phosphonic acid. The carboxylate accomplished through a convergent approach. The key ion generated in the presence of a base such as triethyl- steps in this synthesis involved the preparation and the amine or diisopropylethylamine (DIPEA) attacks a phos- coupling of tripeptide Glp-Glu(OBn)-Asp(OBn)-OH (28) . phorus atom in 8 and forms mixed anhydride 15 which is and tripeptide hydrochloride salt (HCl H2N)2-DAS- then attacked by the amine 13 to result in the peptide 14 [Lys(Cbz)-OBn]2 (29). Several coupling reagents were in- (Scheme 3). Several tripeptides including Cbz-Gly-Phe- vestigated in order to reduce the amount of epimerization Gly-OEt (99%), Cbz-Val-Tyr(tBu)-His-OMe (76%), Cbz- and yield of fragment coupling. T3P, in the presence of di- D-Phe-Phe-His-OMe (71%), Cbz-Gly-Thr(tBu)-Phe-OMe isopropylethylamine, condensed the two peptidyl frag-

Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1573

T3P in EtOAc DIPEA H CH Cl N COOMe 2 2 CbzHN CbzHN COOH + H2N COOMe 0 °C, 1 h O 85% 16 17 18

T3P in EtOAc DIPEA H + CH2Cl2 N COOMe H2N COOMe CbzHN CbzHN COOMe 0 °C, 1 h O 68% 19 20 21

T3P in EtOAc O COOH DIPEA + CH2Cl2 N COOMe NHCbz 0 °C, 1 h H N H2N COOMe NHCbz H N 89% H 22 23 24

Scheme 4 Coupling of sterically hindered amino acids

Lys(Cbz)-OBn T3P in EtOAc ClH·H2N Ph Et3N OH OH H 2 Glp-Glu(OBn)-Asp(OBn)-OH + DAS CH2Cl2 N COOMe Lys(Cbz)-OBn + F3C ClH·H2N F3C COOH r.t. H2N COOMe O 28 29 95% Ph T3P, DIPEA 0 °C to r.t. 25 26 27 86%

Scheme 5 Coupling of an amino acid with a free hydroxy acid Glp-Glu(OBn)-Asp(OBn) Lys(Cbz)-OBn DAS Glp-Glu(OBn)-Asp(OBn) Lys(Cbz)-OBn

30 ments 28 and 29 to form the oligopeptide 30 in satisfactory yields. Scheme 6 illustrates a brief compari- H2N O son of various coupling agents, including the commonly OH H2N OH used carbodiimides and phosphonium-type reagents, and O O NH O the extent of racemization in the fragment coupling of 28 HO Glp 5 DAS and 29. (S)-2-pyrrolidone-5-carboxylic acid (2S,7S)-diaminosuberic acid The combination of T3P and pyridine was employed for 6 amide formation from protected amino acids whose acti- Coupling agent Yield (%) Rate of epimerization vated derivatives were sensitive to racemization. The re- T3P 86.6 1.8 DCC/HOBt 60.5 5.9 action of N-Cbz-alanine and N-Cbz-phenylglycine with EDC/HOBt 67.3 11.1 aniline and benzylamine, respectively, provided anilides TBTU 53.2 9.1 HBTU 65.6 16.1

31, 32 and 33 in high yield without epimerization (Figure PyCloP 4.1 – Downloaded by: National University of Singapore. Copyrighted material. 3). However, the coupling of N-Ac-Ala-OH with aniline PyBOP 63.4 14.2 in the presence of T3P and pyridine was accompanied by Scheme 6 Fragment coupling employing T3P azlactone byproducts as well.

Segment coupling and head-to-tail cyclization of short peptides is a significant area of study in the synthesis of H H H N N N peptides. In this context, coupling agents derived from CbzHN CbzHN CbzHN HOBt and HOAt such as HBTU and HATU have proven O O O to be efficient in both the segment coupling and cycliza- 31 32 33 tion. Similarly, the efficacy of T3P, as demonstrated by 7a 90% 91% 94% Wenger in the synthesis of cyclosporine, prompted > 99:1 er > 99:1 er > 99:1 er Henklein and co-workers7b to evaluate its utility for seg- Figure 3 Amides prepared by employing T3P in combination with ment coupling and cyclization. They carried out a com- pyridine parative study of the usage of T3P and HAPyU in the segment coupling and head-to-tail cyclization of short peptides.7b Thereby it was inferred that T3P is an effective

© Georg Thieme Verlag Stuttgart · New York Synthesis 2013, 45, 1569–1601 1574 Basavaprabhu et al. REVIEW reagent in the relatively demanding cyclization of penta- Table 1 Selected Examples of Amino Acid Azides 34 Prepared peptides and is particularly efficient for systems having Using T3P as Activator sterically hindered amino acids including Aib, (N-Me)Ala Acid azide Yield (%) Acid azide Yield (%) and (N-Me)Phe, at the cyclization site. HAPyU-mediated cyclization yielded the C-terminally epimerized cyclic MeS product whereas T3P afforded the desired stereo-retained N3 all-L cyclic monomer as the major product. The penta- FmocHN 94 84 N3 peptides (Ala)2-MeAla-(Ala)2, Arg-Lys(Ac)-Ala-Val-Tyr, O FmocHN O Arg-Lys(Ac)-(Hmb)Ala-Val-Tyr, Aib-Ala-(Ala)3-OH, MeAla-(Ala)4-OH, MePhe-Ala-(Ala)3-OH, and CbzHN HO (Tmob)Ala-(Ala) -OH [where Ac = acetyl, Hmb = 2-hy- 4 4 N3 84N3 70 droxy-4-methoxybenzyl, and Tmob = 2,4,6-trimethoxy- FmocHN FmocHN benzyl] were studied for head-to-tail cyclization in the O O presence of T3P and the yields reported were satisfactory. Ot-Bu

N3 86 91 FmocHN N3 CbzHN 3.2 Synthesis of Amino Acid Derivatives and O Peptidomimetics O

3.2.1 Synthesis of N-Protected Amino Acid Azides and α-Ureidopeptidomimetics isolated in good yield (Figure 4).8a The T3P-mediated Sureshbabu and co-workers reported the conversion of N- one-pot scheme proves to be more useful with regard to protected amino acids 12 into the corresponding acid the preparation of Boc- and Cbz-protected α-ureidopep- azides 34 by employing T3P (Scheme 7).8a In this proto- tides as their acid azides are not stable to isolation. No col, T3P was used as an acid-activating agent where it racemization was observed by 1H NMR analysis of the formed an anhydride that, upon treatment with sodium α-ureidopeptide esters Fmoc-Phe-ψ[NHCONH]-L-Ala- azide in dimethylsulfoxide, afforded the corresponding OMe and Fmoc-Phe-ψ[NHCONH]-D-Ala-OMe, where acid azide in good yields (Table 1). Acid azides of Fmoc- they exhibited distinct methyl group doublets in the 1H amino acids are isolable and shelf-stable solids,8b unlike NMR spectrum. their Boc- and Cbz-protected counterparts. However, α Cbz-Phe-CON3 and the acid azide of N -Cbz-protected R1 O R2 aspartic acid 5-oxazolidinone were also isolated as sol- PgHN N N COOMe ids.8c H H The use of T3P was extended to the one-pot synthesis of 35 Pg = Fmoc, R1 = Me, R2 = i-Pr (92%) N-protected α-ureidopeptidomimetics 35 starting from 1 2 Pg = Fmoc, R = H, R = -(CH2)3- (88%) 1 2 amino acids through the Curtius rearrangement of the in Pg = Cbz, R = -(CH2)3-, R = CH2SBn (82%) Pg = Cbz, R1 = Bn, R2 = s-Bu (87%) situ generated acid azide followed by coupling of the iso- Pg = Boc, R1 = i-Bu, R2 = i-Pr (80%) 1 2 cyanate with an amino acid ester. The conversion was ac- Pg = Boc, R = Ph, R = Bn (85%) complished under ultrasonication. A series of α- Figure 4 N-Protected α-ureidopeptides ureidopeptides with different Nα-protecting groups were Downloaded by: National University of Singapore. Copyrighted material.

1 NaN R R1 Et3N, Na2S 3 MeCN Et3N, THF N3 SH PgHN PgHN 0 °C 0 °C O T3P 34 O 37 NH2OH·HCl 1 Me NHMe(OMe)·HCl R1 MeCN R R1 O DBU, MeCN )))) NHOH PgHN COOH N 0 °C to r.t. PgHN PgHN Me 12 36 O O one-pot Lossen 38 rearrangement or R1 O R2 R1 DIPEA, THF one-pot Curtius NaBH4 (aq) rearrangement OH PgHN N N COOMe PgHN 0 °C H H 35 Pg = Fmoc, Boc or Cbz 39 R1 = amino acid side chain

Scheme 7 Synthesis of amino acid derivatives employing T3P

Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1575

3.2.2 Synthesis of Amino and Peptide Thioacids

H2N COOMe Thioacids find wider utility in synthetic organic chemistry 41 as well as in polypeptide and protein synthesis through na- 9 DIPEA, HOBt I2, 4 Å MS tive chemical ligation techniques. Thioacids are general- in DMSO DMSO ly prepared by the activation of an acid with carbonyldiimidazole (CDI) or EDC or by way of a mixed r.t. anhydride followed by treatment with sulfur donors such as sodium sulfide, hydrogen sulfide or lithium sulfide. Fmoc-L-Phg-SH Fmoc-D-Phg-SH α 42 The synthesis of N -protected amino or peptide thioacids 43 37 and 40 (Scheme 7 and Figure 5) starting from the corresponding amino or peptide acids employing T3P and sodium sulfide in the presence of triethylamine was recently 10 H reported by Sureshbabu and co-workers. H N COOMe N COOMe FmocHN FmocHN O O R1 O H N 44 PgHN SH 45 O R2 Scheme 8 Racemization study using Fmoc-Phg-L-Ala-OMe (44) 40 and Fmoc-D-Phg-L-Ala-OMe (45) Pg = Fmoc, R1 = Bn, R2 = Me (92%) 1 2 Pg = Fmoc, R = CH2COOPh, R = i-Pr (85%) 1 2 Pg = Cbz, R = i-Pr, R = i-Bu (88%) Pg = Cbz, R1 = CH(Me)OPh, R2 = Bn (82%) L D 1 2 derived from Fmoc-protected - and -Ala confirmed that Pg = Boc, R = s-Bu, R = CH2COOPh (82%) 1 2 Pg = Boc, R = H, R = -(CH2)3- (84%) the protocol was free of racemization. Figure 5 Nα-Protected peptide thioacids 3.2.4 Synthesis of N-Protected Amino Acid Esters The reaction was carried out at 0 °C in acetonitrile. The The preparation of amino acid esters is one of the most protocol holds good for simple as well as bifunctional widely used protocols in peptide chemistry.13a There are amino acids. The hydroxy group of Boc-Ser-OH remained many methods available for esterification, including the unaffected but the thioacid was obtained in rather low application of specific esterifying reagents such as 2-eth- yield. Compounds 42 and 43 thus prepared were further oxy-1-(ethoxy carbonyl)-1,2-dihydroquinoline (EEDQ), converted into Fmoc-L-Phg-Ala-OMe (44) and Fmoc-D- 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquin- Phg-Ala-OMe (45) using the conditions described by oline (BBDI), molecular iodine, cyanuric chloride and 11 Danishefsky and Wang (I2, DIPEA, HOBt, DMSO, r.t.). iron(III) chloride. T3P brings about esterification in an ef- The diastereomers 44 and 45 were subjected to HPLC fective manner by serving as an acid activator.13b Amino analysis and determined to be optically pure (Scheme 8). acids with simple (Phe) and bifunctional (Tyr, Asp) side chains were converted into the corresponding esters 46 3.2.3 Reduction of N-Protected Amino Acids and upon reaction with ethyl, tert-butyl, hexyl and cyclohexyl Peptides to Alcohols alcohols (Table 2). Aminols or peptide alcohols are useful building blocks for Table 2 Nα-Protected Amino Acid Esters 46 the synthesis of oxymethylene peptides and oligopeptidyl R1 Downloaded by: National University of Singapore. Copyrighted material. carbamates. γ-Amino alcohols serve as precursors for the OR2 construction of α,β-unsaturated peptidomimetics and sev- PgHN O eral heterocycles. The synthesis of aminols generally in- 46 volves initial activation of the carboxylic acid followed by reduction using moist sodium borohydride. T3P has been Pg R1 R2 Yield (%) used for the carboxylic acid activation.12 The protocol involved reaction of the N-protected amino acid with T3P in Fmoc CH2C6H4Ot-Bu c-Hex 91 ethyl acetate, in the presence of diisopropylethylamine, at Fmoc CH2C6H4Ot-Bu n-Bu 78 0 °C. The resultant mixture was then treated with moist sodium borohydride to afford the corresponding alcohol Fmoc CH2C6H4Ot-Bu n-Hex 85 39 in good yields (Scheme 7). The protocol was extended Cbz Bn t-Bu 76 to γ-amino alcohols from the corresponding β-amino acids as well. γ-Amino alcohols were obtained in 84–96% Cbz CH2CO2t-Bu Et 79 yield. Chiral HPLC analysis of the enantiomeric aminols

4 General Applications (Equation 1) NH2 O O T3P in EtOAc R R Et3N N acyl azides, OH + H amides 60 °C N carbamates, N ureas 47 48 49 heterocycles R = H (87%), 4-OMe (92%), 4-CN (93%), 2-Me (81%) rearrangement reactions O Me O T3P in EtOAc HN O OH + Et3N N P O O 60 °C Me hydroxamic O nitriles, 85% acids P P isonitriles 50 51 52 O O Scheme 9 Coupling of substituted aromatic and heteroaromatic acids with primary and secondary amines imidazopyridines, dihydropyrimidinones drugs

dine)ethyl] with the pyrimidine nucleobase thymine-1- esters ylacetic acid (54) was accomplished using T3P in N,N-di- named reactions β -lactams methylformamide in the presence of N-ethylmorpholine Equation 1 (NEM) to obtain 55 with a yield of 77%. The product 55 on hydrolysis yielded Dde-protected peptide nucleic acid 16 4.1 As a Carboxylic Acid Activator (PNA) monomer (Scheme 10). In order to preserve the chirality in the target molecule, (S)-malic acid derived 57 was coupled to amine 56 using 4.1.1 Amide-Bond Formation T3P in the presence of diisopropylethylamine at room The amide bond is the most commonly found linkage in temperature.17 The resulting amide 58 was obtained in molecules including macromolecules of biological signif- 86% yield, and was finally converted into ‘upenamide’, an icance. The American Chemical Society’s Green Chemis- alkaloid, through a multistep protocol (Scheme 11). try Institute found that ‘amide formation, avoiding poor atom economy reagents’ is a key aspect for the success of 14a synthesis. The amide moiety, apart from being most OBn common in molecules of pharmacological interest, also OTIPS OBn serves as a starting moiety for several conversions. For NH2 T3P in EtOAc amide-bond formation, commonly followed protocols in- DIPEA OTIPS 56 THF volve activation of the carboxylic acid by converting the + 'upenamide' r.t., 16 h HO O O hydroxy group of the acid into a good leaving group prior 86% NH to treatment with an amine. For the construction of an O O amide bond, a plethora of coupling reagents are avail- O 58 able.14b–d However, choice of the coupling reagent is of O significance and needs to consider not only the portfolio 57 of reactivity but also the simplicity of product isolation. The formation of anilides 49, or substituted benzanilides Scheme 11 Synthesis of ‘upenamide’ intermediates such as 52, is not easy and is dependent on the reactivity Downloaded by: National University of Singapore. Copyrighted material. of the acid, which is in turn determined by the nature of The synthesis of 4-aminoimidazoles 62 was carried out the substituent on the aromatic ring. Thus the acids 47, in starting from 1-substituted 4-nitroimidazoles 59. The lat- the presence of T3P and triethylamine at 60 °C, was cou- ter was subjected to catalytic hydrogenation using palladi- pled with aniline 48 to afford the anilides 49 (Scheme 9).15 um on carbon to obtain unstable 4-aminoimidazole 60 N-Acylation of ethyl 2-N-Dde-aminoethylglycinate 53 which was immediately acylated with an acid employing [where Dde = 1-(4,4-dimethyl-2,6-dioxocyclohexyli- T3P and triethylamine (Scheme 12).18

O HN

HN T3P in DMF O N H hydrolysis Dde-protected N COOMe + NEM Dde-HN O PNA monomer O N r.t., 16 h O 77% N 53 COOH Dde-HN OMe 55 54 Scheme 10 Synthesis of Dde-protected PNA monomer

Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1577

N H (50 psi) 4.1.2 Esterification 2 N NO2 Pd/C N NH2 1 N Keto phosphonate 69, required for the preparation of α-al- R EtOAc 1 R kylidene-γ-butyrolactones 70, was obtained by the reac- 59 60 tion of commercially available 4-hydroxy-2-

R2COOH (61) O cyclohexenone (67) and diethylphosphonoacetic acid (68) N T3P in EtOAc, Et3N in the presence of T3P in anhydrous dichloromethane at N R2 20 CH2Cl2, –10 °C N H R1 0 °C to room temperature. This was the crucial step in 32–72% 62 the preparation of α-alkylidene-γ-butyrolactones 70 (Scheme 14). Scheme 12 Synthesis of 4-aminoimidazoles

O O OEt T3P The synthesis of N-hydroxyamides relies on the acylation EtO OH P CH2Cl2 of N- and O-alkylhydroxylamines and T3P has been found + O O 0 °C to r.t. to be selective in N- over O-acylation with ambident nu- OEt OH O cleophiles such as phenolic amines and hydroxylamine. P OEt O O The reaction of alkyl hydroxylamine 63 with an acid in the 67 68 69 presence of T3P and triethylamine afforded only the N-acylated products (N-hydroxyamides) 64 in 36–61% yield.19 On the other hand, with reagents such as DCC and EDC- HOBT, O-acylation occurred exclusively (Scheme 13). O O O acylation 70 Ph t-Bu Si O Scheme 14 Preparation of keto phosphonate 70 N OH Ph H 63

RCOOH (61) RCOOH (61) The utility of T3P was extended to the esterification of T3P CH2Cl2 EDC-HOBt porphyrin 71 by reaction with 3-(1-pyrrolyl)propan-1-ol Et3N, CH2Cl2 r.t. r.t. (72) to afford the electropolymerizable porphyrinoid met- Ph Ph O 21 t-Bu Si O O R al complex 73 (Scheme 15). The usage of T3P here rep- t-Bu Si O N N R Ph H resents a facile route for the preparation of immobilizable Ph O 64 OH 65 porphyrinoid metal complexes, mainly owing to its operational simplicity. Scheme 13 Synthesis of N-hydroxyamides

The preparation of alcohols from the corresponding car- T3P in EtOAc, N N boxylic acids 61 was reported by Sureshbabu and co- Et3N, THF workers12 employing T3P as an acid activator followed by Co N N N N 2 OH N reduction using moist sodium borohydride (see also sec- Co 72 tion 3.2.3). The alcohols 66 were obtained in 80–93% N N 0 °C to r.t. yields (Figure 6). 55% O O O O

R OH COOH Downloaded by: National University of Singapore. Copyrighted material. 66 COOH N N

71 73 R = O N 2 Scheme 15 Synthesis of metalloporphyrin derivatives 83% 91% 89%

4.1.3 Radical Precursor Synthesis

O2N The growing need for the radical precursors required in the preparation of N-acyloxy-substituted thiazolethiones 80% 90% 93% 76 and pyrimidinethiones 77 in synthetic and bioorganic

Br chemistry has led to the development of many routes for their synthesis. In an earlier report,22a–c the isolation of 92% highly labile O-acylthiohydroxamates led to a severe drop Figure 6 Alcohols prepared employing T3P in yields as their recrystallization was not practicable and purification by column chromatography was associated with substantial loss of the product. In general, the synthe-

© Georg Thieme Verlag Stuttgart · New York Synthesis 2013, 45, 1569–1601 1578 Basavaprabhu et al. REVIEW sis of N-acyloxy-substituted thiazolethiones involves the choice of the activation method or reagent or by O-protec- reaction of N-hydroxythiazolethiones 74 or N-hy- tion. The reported protocols in this regard involve treat- droxypyridinethione 75 with a carboxylic acid 61 in the ment of oleyl chloride with hydroxylamine hydrochloride, presence of a dehydrating agent. Several attempts were but they still gave low yield (42–61%).23a The underlying made in this direction using DCC and acid chloride meth- problem in the hydroxyamidation is the presence of an ods, but they failed to afford the desired compounds in ac- acidic oxygen atom that gets activated through deproton- ceptable yields. In this context, T3P was explored as a ation. Exclusive N-acylation has been achieved by using dehydrating agent by Hartung and Schwartz,22d who acid chlorides in the presence of magnesium oxide,23b but found that T3P (1.5 equiv) in the presence of 1,4-diazabi- this method has been limited to Fmoc-amino acid chlo- cyclo[2.2.2]octane (DABCO) afforded 76 and 77 in satis- rides and thus does not seem to have a widespread utility. factory yields (Scheme 16 and Table 3). In this context, T3P has been found to be extremely useful for efficient preparation of hydroxamic acids not only S without O-acylation, but also without the prerequisite for S 23c N O-protection. Appendino and co-workers exploited the R2 R2 OH O difference in nucleophilicity between the nitrogen and ox- 74 N S ygen atoms of hydroxylamine to accomplish exclusively R1 O 20–40 °C N-acylation using T3P. Hydroxyamidation of oleic acid S 76a–h worked well in acetonitrile at room temperature, whereas O T3P comparatively lower yields of 41% and 53% were record- base R1 OH ed when dichloromethane and ethyl acetate, respectively, CH2Cl2 N S 61 OH O were used. A 50% solution of T3P in ethyl acetate (1.2 75 N equiv) and 2.0 equivalents of hydroxylamine hydrochlo- R1 O 0–20 °C ride led to the conversion of acid into hydroxamic acid S 77a,b with 52–85% yields (Table 4). T3P was also found to be useful in the preparation of carbamates (Boc- and Cbz- Scheme 16 Synthesis of N-acyloxythiazol-2(3H)-thiones 76 and N- protected aromatic amines)24 79 and 80 from the hy- acyloxypyridine-2(1H)-thiones 77 droxamic acid 78 (Scheme 17) through Lossen rearrangement. 4.1.4 Hydroxyamidation The typical route for this purpose is the reaction of car- 4.1.5 Weinreb Amide Synthesis boxylic acids with hydroxylamine. Generally, hydroxy- 25 amidation of carboxylic acids is carried out using O- Since their initial appearance in 1981, Weinreb amides protected hydroxylamine derivatives such as O-benzylhy- have been considered as useful substrates in organic syn- droxylamine or tetrahydropyran-protected hydroxyl- thesis owing to their reduction into aldehydes and their amine. The reaction of unprotected hydroxylamine with utility in the preparation of ketones upon reaction with acids, in the presence of DCC or EDC is not chemoselec- Grignard reagents. Their utility has been demonstrated in peptide chemistry as well.26 T3P served as an efficient active as it yields O-acylated products as well. The undesired O-acylation can be circumvented by the appropriate

Table 3 N-Acyloxythiazol-2(3H)-thiones 76 and N-Acyloxypyridine-2(1H)-thiones 77

Product R1 R2 Base Temp (°C) Time Yield (%) Downloaded by: National University of Singapore. Copyrighted material.

76a 4-ClC6H4 Me pyridine 20 10 min 74

76b 4-ClC6H4 Me DABCO 20 10 min 89

76c 4-ClC6H4 t-Bu C5H5N 20 10 min 60

76d 4-ClC6H4 t-Bu DABCO 41 15 min 75

76e 4-ClC6H4 Ph pyridine 20 10 min 51

76f 4-ClC6H4 Ph DABCO 41 10 min 81 76g Me Me DABCO 41 72 h 83

76h Me t-Bu DABCO 41 12 h 75

77a Me – DABCO 0 4 h 82

77b t-Bu – DABCO 20 10 min 83

Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1579

T3P in EtOAc Et3N NHCbz –30 to 30 °C O T3P in EtOAc O Et3N, NH2OH⋅HCl BnOH OH 79 OH MeCN N H r.t. T3P in EtOAc Et3N 50 –30 to 30 °C 78 NHBoc t-BuOH

Scheme 17 Conversion of hydroxamic acid into N-protected anilines

T3P in EtOAc O Table 4 Hydroxyamidation of Carboxylic Acids O Et3N, K2CO3 (aq) LiO N NH(OMe)Me N N Boc MeO Boc Hydroxamate Yield (%) CH2Cl2 O 85% O

H 81 82 N OH 85 6 5 PhMgBr O 98% O THF, r.t. H R N NH OH 13 77 O O O N H Boc N 1 3 R R O 6 OH 85 2 O R 83 H 84 N OH 4 3 70 Scheme 18 Synthesis of morpholine derivatives (serotonin and nor- OH O adrenaline reuptake inhibitors) 84 H N 6 9 OH 72 O Glycosylated peptides and proteins play an important role

O in biological processes and are popular targets in drug de- 28 OH sign. T3P was employed to convert the γ-carboxyl group N 72 H of protected glutamate 85 into its Weinreb amide 86 in the O presence of N-ethylmorpholine. This was one of the cru- OH N 57 cial steps in the synthesis of C-glycosylated amino acid H 88. The amide 86, upon reduction, yielded aldehyde 87 O which was further converted into 88 (Scheme 19). OH N 52 H OMe Me HCl⋅NH O OH Me O N O OMe T3P in EtOAc 56 NEM, MeCN N OH

H Downloaded by: National University of Singapore. Copyrighted material. r.t. BocHN COOMe BocHN COOMe O 92% OH 85 86 N H O O H 64 DIBAL–H

HO 62% BocHN COOMe

OBn tivator in Weinreb amide formation from the correspond- O COOMe ing acids. Importantly, the usage of T3P minimizes the BnO BnO OBn rate of epimerization at the α-carbon. NHBoc 88 Fish et al.27 treated the lithium salt of acid 81 with T3P, triethylamine and N,O-dimethylhydroxylamine to afford Scheme 19 Stereoselective synthesis of a C-glycosidic analogue of Weinreb amide 82 (Scheme 18). The latter was further N-glucoasparagine converted into ketone 83 through a Grignard reaction.

O 2-Deoxyribose and its derivative 89 serve as useful com- T3P in EtOAc N EtOAc pounds in the preparation of chiral building blocks, for in- R stance in the preparation of (+)-diplodialides B and C 45–65 °C 94–96% (92a,b). For example, the acid 90, in the presence of T3P 93 94 and triethylamine, was converted into Weinreb amide 91 R = OH, ONH , NH in 77% yield; the latter was then utilized to obtain the di- 4 2 plodialides (Scheme 20).29 Recently, to obtain good yields Scheme 21 Synthesis of nitriles from amides, acids and ammonium of the amides without column purification, Sureshbabu salts and co-workers fine-tuned the reaction conditions for the synthesis of Nα-protected amino and peptide acid derived Weinreb amides 38 using T3P.30 N Cbz CN

T3P, Et3N HO 95 NH(OMe)Me > 98% ee O OH OMe MeCN O O t r.t. Figure 7 Structure of Cbz-Pro-CN (95) Ph2Bu Si HO 77% 89 90 imes, which do not possess an acceptable level of stability Me for isolation. Augustine et al.32 employed T3P for the N chiral 5-carbon OMe building block above conversion in the presence of base and hydroxyl- O O amine hydrochloride at 100 °C (Scheme 22 and Figure 8). Ph2t-BuSi The conversion takes place by attack of the aldoxime hy- 91 droxy group on the phosphorus atom of T3P to form a phosphonate 99 which, upon decomposition, results in O nitrile 96 and phosphonic acid 9.

HO (+)-diplodialides B and C 92a,b O O O P P Scheme 20 Synthesis of chiral building blocks from a deoxyribose O O P O .. 4.2 As a Dehydrating Agent O OH NH2OH⋅HCl N

R H Et3N R H 4.2.1 Preparation of Nitriles and Isonitriles 97 98 Nitriles serve as versatile synthetic intermediates in the manufacture of a variety of compounds that include phar- O O O O O O OH maceuticals, agricultural chemicals and dyes. A common N P P P route to access nitriles is the dehydration of primary am- R CN ides. For this purpose, several reagents have been report- R H 9 96 ed, among them inorganic cyanide ions, phosphorus 99 pentoxide, titanium(IV) chloride, Burgess reagent, N- chlorosuccinimide with triphenylphosphine, phosphorus Scheme 22 Mechanism for the preparation of a nitrile from an alde- Downloaded by: National University of Singapore. Copyrighted material. oxychloride, thionyl chloride and trifluoroacetic anhy- hyde employing T3P dride. In recent years, protocols involving the use of reagents such as PyBOP, EDC and cyanuric chloride have R N also been reported. Several of the above reagents possess 96 CN intrinsic constraints for scale-up and industrial applica- CN CN 31 tions. Meudt et al. used T3P for the conversion of 93 into CN S the nitrile 94 (Scheme 21). Cbz-protected prolinamide was also converted into its nitrile 95 with 98% ee (Figure 91% 94%94% 95% 7). The other products formed in the process are water- soluble and thus make the product isolation easier. Figure 8 Selected examples of nitriles synthesized from aldehydes Nitriles 96 can also be made starting from aldehydes 97 In the case of acid-sensitive groups, 2.0 equivalents of with or without the isolation of the intermediate aldoxime base was employed. Decreasing the reaction temperature 98, followed by its conversion into the nitrile in the pres- and the amount of T3P (from 1.1 to 0.8 equiv) lowered the ence of a suitable dehydrating reagent. Several protocols yield of the corresponding nitrile. Among the various have been devised to circumvent the isolation of aldox- bases examined (Et3N, DBU, NaOAc, DABCO and

Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1581

DIPEA), triethylamine gave better results. N,N-Dimethyl- Formamides 100 were dehydrated to isonitriles 101 using formamide and N,N-dimethylacetamide (DMA) were the T3P at 55 °C (Scheme 23).33 best solvent systems for this conversion. Aliphatic, aromatic and heteroaromatic aldehydes yielded H T3P in EtOAc nitriles in 94–99% yields. The protocol can also be ap- N O EtOAc NC plied to the substrates having cyano, methoxy, halo, nitro, H 55 °C boronate and carboxylate groups (Table 5 and Table 6). 97% 100 101 Table 5 Aromatic Nitriles 96 Scheme 23 Synthesis of isonitriles 101 from formamides 100

Nitrile Yield (%) Nitrile Yield (%)

CN CN In this patent, only one amino acid derivative, namely (S)- 98 99 methyl 2-formamido-3-phenylpropanoate, was also dehy- Br drated to its isonitrile 102 (Figure 9) with a crude yield of 99% in the presence of T3P at 28 °C in ethyl acetate. Cl CN O2N CN 98 94 OH F

CN NC CN CN COOMe 98 98 102 99% MeOOC Figure 9 (S)-Methyl 2-isocyano-3-phenylpropanoate CN Br CN O B 94 97 However, its general applicability to amino acid chemis- O MeO try has yet to be demonstrated. A similar strategy was utilized for a tandem conversion of formamide 104 into its

F CN isonitrile and into 2-phenyl-N-(o-tolyl)imidazo[1,2- Me2N CN a]pyridin-3-amine (106) by way of a multicomponent re- 96 96 34 HO action in almost quantitative yield (Scheme 24). F

O T3P in EtOAc N H N H EtOAc 104 NH NH2 90 °C 103 65% N Table 6 Heteroaromatic Nitriles 96 H N O 105 Nitrile Yield (%) Nitrile Yield (%) 106 Scheme 24 An in situ generation of isonitrile and its utility in a mul- N CN N Cl ticomponent reaction 95 98 CN Downloaded by: National University of Singapore. Copyrighted material.

CN CN 4.2.2 Preparation of Alkenes MeOOC 96N 94 Generally, dehydration of an alcohol gives an alkene, but Cl N N H with respect to secondary and tertiary alcohols, harsh con-

CN CN ditions are essential. Meudt and co-workers demonstrated O the utility of T3P for a plethora of conversions. One such 99 97 35 N example is the dehydration of an alcohol. Here, the hy- H droxy group of the alcohol adds to the phosphoryl phos- O CN CN phorus atom of T3P to form an anhydride which is then N 95N 99 converted into the alkene 110 with the expulsion of phos- N S phonic acid 9 (Scheme 25). It can be carried out using pri- Me mary 107, secondary 108 and tertiary alcohols (107–109). Cl CN The reaction conditions were simple and mild, and in-

97N 95 volved easy workup procedures. CN O N Me

4 R T3P in EtOAc Table 7 Effect of Base in the Synthesis of 1,3,4-Oxadiazole 115a R3 OH 1 4 EtOAc R R 1 2 (R = 4-BrC6H4, R = 4-t-BuC6H4) Mediated by T3P 0 °C to r.t., 3 h 1 2 2 3 R R R R T3P (equiv) Conditions Yield (%) 110 107 R1, R2 = alkyl, R3, R4= H 108 R1, R2, R3 = alkyl, R4 = H 1.5 Et3N, 60 °C, 4 h 65 109 R1, R2, R3, R4 = alkyl 2.5 Et3N, 80 °C, 3 h 94 Scheme 25 Alkene formation from alcohols 4.0 Et3N, 80 °C, 3 h 94

In this study, Boc-protected 4-hydroxyproline methyl es- 2.5 Et3N, 110 °C, 0.5 h 93 ter (111) was also subjected to dehydration in the presence 2.5 DIPEA, 80 °C, 3 h 89 of T3P at 0 °C, and dehydroproline 112 was obtained in an excellent yield of 97% with high purity (Scheme 26). 2.5 DBU, 80 °C, 4 h 71 2.5 pyridine, 80 °C, 3 h 92 HO T3P in EtOAc 2.5 pyridine, 110 °C, 0.5 h 91 EtOAc

N COOMe 0 °C to r.t., 3 h N COOMe 2.5 DBU, 25 °C, 6 h trace Boc 97% Boc 111 112

Scheme 26 Dehydration of Boc-protected 4-hydroxyproline methyl ester (111) to dehydroproline 112 N N O R1 2 NH2 O R 4.3 Synthesis of Heterocycles O R2 N H 115 NH2 113 R2 N H N N 4.3.1 Oxa- and Thiadiazoles 113 O R1 R2 Et N (3.0 equiv) S Et N (3.0 equiv) 1 + T3P 3 Heterocycles have gained prime importance in biological 3 R OH EtOAc, 80 °C 117 P2S5 or 61 studies as a large number of drug molecules possess het- Lawesson reagent EtOAc, 80 °C HO erocycles as active subunits. Numerous protocols and re- N agents have been reported for the synthesis of different O N R2 NH 1 2 classes of heterocycles. In the case of 1,3,4-oxadiazoles, 2 R N R 114 the synthesis of this unit is most commonly carried out by 116 the reaction of an activated acid with an acid hydrazide, Scheme 27 Synthesis of 1,2,4- and 1,3,4-oxadiazoles and 1,3,4-thi- followed by dehydrative cyclization of the resultant di- adiazoles acylhydrazide in the presence of a reagent such as thionyl chloride, phosphorus pentoxide, sulfuric acid, p-toluenesulfonyl chloride or phosphorus oxychloride. The ability Table 8 1,3,4-Oxadiazoles 115 of T3P to serve as the coupling and dehydrating agent for the synthesis of 1,3,4-oxadiazoles was studied in detail R1 R2 Yield (%) (Table 7).36 4-BrC H 4-t-BuC H 94 The protocol involves the coupling of acids 61 and acid 6 4 6 4 Downloaded by: National University of Singapore. Copyrighted material. hydrazides 113 to form the diacylhydrazides, which in the 4-BrC6H4 3-MeO-4-HOC6H3 86 presence of T3P (2.5 equiv) and triethylamine (3.0 equiv) N-Boc-azetidin-3-yl 2,4-Cl C H 85 at 80 °C cyclize to 1,3,4-oxadiazoles 115 (Scheme 27 and 2 6 3 Table 8). The products were isolated in good yields. At N-Boc-azetidin-3-yl 5-bromopyridin-3-yl 82 room temperature, only the coupling took place, leading 5-methylthiophen-2-yl t-Bu 91 to a diacylhydrazide that did not undergo cyclization. The versatility of the protocol was demonstrated by using aro- 5-bromopyridin-3-yl H 84 matic hydrazides with various electron-donating and 1-naphthyl 4-BrC H 90 -withdrawing substituents. The protocol was compatible 6 4 with substrates having halo, cyano, hydroxy, methoxy and N-Boc-aminoethyl 4-methyl-1,2,3-thiadiazol-5-yl 88 N-Boc substituents. cyclopentyl 3-Me-4-O2NC6H3 92

3-MeOC6H4 3-Me-4-O2NC6H3 88

N-Boc-aminoethyl 3-FC6H4 85

Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1583

1,2,4-Oxadiazoles 116 were prepared by heating O-acyl- Table 10 1,3,4-Thiadiazoles 117 ated amidoximes in the presence of pyridine, followed by 1 2 dehydrative cyclization mediated by EDC or DCC. It has R R Yield (%) elegantly been demonstrated that they can be prepared by 4-MeC H 3-FC H 92 the reaction of acid 61 and amidoxime 114 in the presence 6 4 6 4 of T3P (2.5 equiv) and triethylamine (3.0 equiv) in ethyl 4-NCC6H4 5-bromopyridin-3-yl 86 acetate at 80 °C (Scheme 27 and Table 9).36 cyclopentyl 3-Me-4-O2NC6H3 93 cyclobutyl t-Bu 87 Table 9 1,2,4-Oxadiazoles 116 isobutyl 3-FC6H4 85 R1 R2 Yield (%) 2-O2NC6H4 t-Bu 90

4-BrC6H4 Ph 96 5-bromofuran-2-yl Me 94

4-BrC6H4 N-Boc-aminoethyl 88 4-trifluoromethyl-β-styryl H 88

4-CNC6H4 6-chloropyridin-3-yl 89 5-methylthiophen-2-yl 5-bromopyridin-3-yl 92

2-methoxy-β-styryl Me 93 the cyclodehydration of the intermediate benzohydrazide 120, as delineated in Scheme 28. 5-bromothiophen-2-yl N-Boc-aminoethyl 91 4.3.2 Imidazo[1,5-α]pyridines and Quinolines The title molecules were generally accessed by the con- The protocol was extended to the preparation of 1,3,4-thi- densation of carboxylic acids and 2-methylaminopyridine adiazoles 117. A one-pot reaction of acid 61 and hydra- in the presence of a dehydrating agent (DCC, HgOAc or zide 113 with phosphorus pentasulfide or the Lawesson I2). T3P, however, led to imidazo[1,5-α]pyridines through reagent in the presence of T3P furnished 117 (Scheme 27 an improved protocol.37 The reaction of an acid 61 and a and Table 10). 2-(aminomethyl)pyridine 123 in the presence of T3P at Thus, unlike in the synthesis of oxadiazoles, the role of room temperature gave the amide 124, which on refluxing T3P in the preparation of 1,3,4-thiadiazoles is limited to in ethyl acetate or n-butyl acetate underwent cyclodehy- the initial coupling reaction and the cyclodehydration dration to yield the corresponding imidazo[1,5-α]pyridine could proceed without the involvement of T3P. This was 125 (Scheme 29). The nature of the substituents on pyri- established by carrying out a control experiment, namely dine did not have a significant effect on the yield of the final products, which were isolated in 72–85% yield.

O O F NHNH2 OH +

118 119 Downloaded by: National University of Singapore. Copyrighted material.

T3P in EtOAc (1.1 equiv) reflux, 2 h Et3N (2.2 equiv) EtOAc O H F N N H O 120 P2S5 P2S5, Et3N (1.2 equiv) T3P in EtOAc (1.2 equiv) T3P in EtOAc (1.2 equiv) P2S5, EtOAc EtOAc, reflux, 5 h reflux, 12 h EtOAc, reflux, 3 h 121 (86%), 122 (5%) 121 (37%), 122 (3%) 121 (89%), 122 (4%)

N N F N N F

O + S

121 122

Scheme 28 Control experiment for the cyclodehydration

R2COOH 2 R NH3 R1 61 H R1 R1 130 T3P in EtOAc N R1 O SiO2 R2 EtOAc or n-BuOAc N N NH2 r.t. to reflux 129 131 N R2 COOMe 123 125 T3P in EtOAc R1 O NH Et3N, CH2Cl2 o N R2 0–5 C H COONa N 75–90% 132 124 COOMe

R1 R2 Time (h) Yield (%) R1 H Ph 96 76 NH CF3 Ph 24 85 Ph Me 3 82 N 2-furyl H 24 75 2 O R H 2-Py 18 72 133 H 2-thienyl 5 78 Scheme 31 Synthesis of β-lactams 133 Scheme 29 Synthesis of imidazo[1,5-α]pyridines 125

The same protocol was extended to quinoline systems: the COOMe COOMe synthesis of imidazo[1,5-α]quinoline 128 was found to be NH favored in n-butyl acetate as solvent. However, only two T3P, Et N O 3 NH O O O examples were illustrated (Scheme 30). CH2Cl2 O O O ONa 0–5 °C P P P NaOOC MeCOOH (127) N NH2 T3P in EtOAc N R N 132 134 R n-BuOAc O O O –O O O ONa r.t. to reflux, 3 h R1 P P P

128 N 126 R2 131 R = cyclopentyl (73%) R = Bn (66%) COOMe

1 Scheme 30 Synthesis of imidazo[1,5-α]quinolines 128 NH R

4.3.3 β-Lactams N O R2 β-Lactams play a crucial role as antibacterials and show an array of bioactivities including inhibition of serine, 133 cysteine, and HIV-I proteases. They are synthesized Scheme 32 Reaction mechanism for the formation of β-lactams through the [2+2] cycloaddition of ketene with an imine under photochemical conditions. They have also been pre- 4.3.4 Biginelli Reaction pared by the annelation of acid chlorides or their equivalents with imines (a variant of the Staudinger reaction). β- Dihydropyrimidinones are pharmaceutically relevant

Lactam derivatives were prepared in fairly good yields compounds with antibacterial and anti-inflammatory ac- Downloaded by: National University of Singapore. Copyrighted material. employing Schiff bases derived from phenylglycine and tivities. Biginelli developed a simple protocol for their cinnamaldehyde; however, this was associated with synthesis that involves the reaction of an aldehyde, a β- epimerization of the chiral center during imine formation. keto ester, and a urea or thiourea. Several modifications Usually, the ketene required for the [2+2] cycloaddition have been made in the Biginelli reaction to enhance the was obtained by activation of the corresponding carboxyl- yield and to optimize the conditions for industrial usage. ic acid with p-toluenesulfonyl chloride, ethyl chlorofor- Recently, Kappe et al.39 made use of polyphosphate ester mate, cyanuric chloride, trifluoroacetic anhydride or N,N- (PPE) as a promoter for the Biginelli reaction. As poly- bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride. phosphate ester is not commercially available, it needs to be prepared freshly whenever required. Kappe et al. inves- Recently, Crichfield et al.38 used T3P as a carboxylic acid tigated the mechanism of the Biginelli reaction, which activator for the preparation of ketene. The ketene formed they found proceeded through an N-acyliminium ion in- from 132 underwent [2+2] cycloaddition with imine 131 to produce the corresponding 2-azetidinones 133 (Scheme termediate. The dehydrating properties of polyphosphate 31 and Scheme 32). ester in combination with an aprotic solvent such as tetrahydrofuran drive the reaction in the desired pathway and minimize the side reactions associated with the earlier protocols. It was envisaged that a phosphorus-containing

Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1585 reagent with dehydrating properties would be of interest.40 minutes under microwave irradiation at 100 °C (Scheme Interactions between the phosphorus of polyphosphate es- 35). ter and the N-acyliminium ion drives the reaction through a stabilized enol-phosphate intermediate, which eventual- NHNH2 O R ly prompted the selection of T3P as a promoter. The mix- T3P in EtOAc R + ture containing an aldehyde 97, a urea or thiourea 136 and MW, 100 °C N an active methylene compound 135 was refluxed in ethyl 75–98% H 140 141 142 acetate in the presence of T3P (Scheme 33). The reaction R = 2-Me (76%), 3-Cl (87%), 4-CF3 (86%), 2-Cl (92%), was clean and the final products 137 were obtained in 4-Br (98%), 4-Me (84%), 4-F (94%), 4-OMe (82%) good yields (60–86%). Aldehydes with electron-donating groups resulted in lower yields than those with electron- Scheme 35 Synthesis of indole derivatives 142 withdrawing groups. A variety of ketones and aldehydes were used as sub- R2 2 strates, and the reaction proceeded well in all cases. Un- T3P in EtOAc O R O H O (1.0 equiv) branched ketones furnished products in 76–82% yields R1 NH R1 97 EtOAc after heating at 110 °C. Cyclic and branched ketones re- + reflux N X quired a higher reaction temperature (150 °C). T3P medi- O H NH2 ates the Fischer indole synthesis by initially acting as a 135 137 H2N X water scavenger, whereby it drives the equilibrium to- 136 R1 = OEt, X = O wards the formation of hydrazone 145. During this pro- 2 R = Ph (77%); 4-O2NC6H4 (74%) cess, T3P produces phosphonic acid, which functions as a 4-ClC6H4 (69%); 3-ClC6H4 (86%) proton source to accelerate ring closure to form 142 3-F3CC6H3 (73%) R1 = OEt, X = S, R2 = Ph (80%) (Scheme 36). R1 = Me, X = S, R2 = Ph (72%) Bis(indolyl)methanes 149 (Figure 10) were also synthe- Scheme 33 One-pot Biginelli reaction sized by the reaction of indole with an aliphatic or aromatic aldehyde or ketone in the presence of T3P (10 mol%) at S-Alkyl imidazoles 139 was also prepared by the cyclode- room temperature.43 hydration of 138 in the presence of T3P in ethyl acetate at reflux with a yield of 91% (Scheme 34).41 R

NH SMe H N 2 SMe T3P in EtOAc N O EtOAc reflux, 2 h N COOEt N COOEt 3 H N 3 H 91% H 139 138 149 R = H (91%), 2,4-OMe (90%), 4-Me (93%) . Scheme 34 Synthesis of S-alkyl imidazole derivatives 139 Figure 10 Bis(indolyl)methanes 149 4.3.5 Fischer Indole Synthesis 4.3.6 4-Thiazolidinones Indole is an important structural unit present in natural products as well as in therapeutically relevant compounds. 4-Thiazolidinones44 152 exhibit a wide range of biologi-

The Fischer indole synthesis continues to be a dominant cal activities including antiviral, antiasthmatic and antimi- Downloaded by: National University of Singapore. Copyrighted material. route to accessing indoles, and has been used successfully crobial activities. General methods for their preparation in combinatorial chemistry. Conversion of arylhydra- involve the cyclocondensation of aldehydes, amines and zones into indoles 142 is catalyzed by Bronsted acids, mercaptoacetic acid 151 in one pot in the presence of a Lewis acids and solid acids like montmorillonites and ze- catalyst. Rangappa and co-workers45 reported a one-pot olites. Odell and co-workers42 developed an operationally protocol for their preparation employing alcohols 150, simple one-pot protocol using T3P. The reaction between amines 130 and 151 using a combination of T3P and di- various arylhydrazines 140 and cyclohexanone (141) in methyl sulfoxide as the oxidant as well as the cyclodehy- the presence of T3P (1.25 equiv) afforded 142 within five drating agent (Scheme 37).

O O O P P O O P NH H O HN O O O N O O O OH NH NH2 8 HN O HN P P P NH H OH 145 144 141 140 143 [3,3]-sigmatropic shift 9

H H

NH NH N NH2 NH H NH2 148 147 146

N H 142

Scheme 36 Mechanism for the T3P-mediated indole synthesis

R3NH O O O O 1 3 T3P in EtOAc O O O O Me R 130 (2.5 equiv) P P P S OH EtOAc–DMSO 3 N S 2 + R Me .. R R2 0 °C to r.t. HO 150 1 R2 HS COOH R 1 151 152 R 153 O 150 R1 = H, R2 = Ph, R3 = Ph (92%) 1 2 3 P R = H, R = 4-HOC6H4, R = 3,5-(MeO)2C6H3 (93%) O O O O O R1 = H, R2 = 2-O NC H , R3 = 4-MeOC H (94%) O HO O O O 2 6 4 6 4 P P P R1 = H, R2 = 4-F CC H , R3 = 2-MeC H (95%) O 3 6 4 6 4 P P O 1 2 3 O R = H, R = Me2NC6H4CH2, R = 4-BrC6H4 (88%) S 1 2 3 Me Me R = Me, R = Ph, R = 3,5-Cl2C6H3 (89%) 8 O H O Me Scheme 37 Synthesis of 4-thiazolidinones S 1 1 2 R R R R2 Me 155 154 Me S Lower yields were recorded when other solvents (toluene, 3 2 R NH2 benzene, chloroform, tetrahydrofuran, acetonitrile and 130 Downloaded by: National University of Singapore. Copyrighted material. 1,4-dioxane) were used. Varying the amount of T3P did R3 COOH N HS COOH H not affect the reaction duration and yield, whereas an in- N 151 3 S R1 R2 R crease in reaction temperature lowered the reaction dura- 2 R1 R tion but also caused a slight decrease in the yield. 156 157 O P Functional groups such as hydroxy, nitro, ester, methoxy O O O P P and Boc were reported to be tolerated under the conditions O O employed. Unlike other routes, this protocol uses an alco- 8 hol as one of the components. T3P in the presence of di- O O O O O O O O OH methyl sulfoxide mediates the oxidation (a modified R3 P P P Swern-type oxidation) with the release of dimethyl sulfide N R3 NH S S and subsequently acts as cyclodehydrating agent to form 2 1 1 R R 2 152 (Scheme 38). R R 9 158 152 Scheme 38 Mechanism for the formation of 4-thiazolidinones 152

Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1587

4.3.7 Friedlander Synthesis of Polysubstituted Quinolines and Naphthyridines O O The Friedlander reaction involves the reaction between an COOEt Cl COOEt o-amino aryl aldehyde or ketone and another aldehyde or 165 O 164 ketone with an active methylene group and leads to the H formation of quinolines, polypyridyl bridging ligands and related bicyclic aza-aromatic compounds. Various proto- N NH2 163 cols have been reported, involving transition-metal catalysts, Lewis acids and Bronsted acid catalysts. However, T3P in EtOAc many of these procedures are not satisfactory with respect 60 °C, 30–60 min to the operational simplicity, cost of the reagent and con- COOEt COOEt 46 ditions involved. Jida and Deprez reported a simple one- Cl pot synthesis of polysubstituted quinolines and naphthyri- N N N N dines employing T3P as a promoter under solvent-free 166 85% 167 87% conditions. The Friedlander reaction of 2-amino-5-chlo- robenzophenone with cyclohexanone under solvent-free Scheme 40 Synthesis of naphthyridines 166 and 167 conditions, employing T3P (1.0 equiv) at 60 °C gave 100% yield of 159 (Figure 11) within 30 minutes. Pyranoquinolines and furanoquinolines are generally accessed through aza-Diels–Alder reactions of imines with dihydropyran (170) or dihydrofuran (171) using transition-metal catalysts. The reaction of an aldehyde 168, an amine 169 and 170 in the presence of T3P (20 mol%) was Cl reported to give pyranoquinolines 172, and the analogous

N reaction with 171 yielded furanoquinolines 173 as a mix- 47 159 ture of cis- and trans-isomers (Scheme 41).

Figure 11 Polysubstituted quinoline 2 2 R R O O + Cyclic monofunctionalized ketones and 2-aminoaryl ke- HN HN tones were employed to obtain tricyclic quinolines. A va- O riety of aromatic, heteroaromatic, bicyclic, and R1 R1 heterobicyclic ketones such as α-tetralone, chromanone, CHO NH2 170 dihydrobenzofuranone and dihydrobenzothiophenone T3P in EtOAc 172a 172b (20 mol%) 2 were subjected to Friedlander annulation with 2-amino- R1 + R THF, r.t. aryl ketone and cyclohexanone to prepare polysubstituted O quinolines 162 in excellent yields (Scheme 39). Various 168 169 R2 R2 functionalized ketones including ethyl pyruvate, diethyl O O 171 HN 1,3-acetonedicarboxylate, tert-butyl acetoacetate and eth- + HN yl acetoacetate also furnished 162. Jida and Deprez also reported the preparation of two naphthyridine derivatives, R1 R1 166 and 167, through the reaction of 2-aminopyridine car- 173a 173b

boxaldehyde 163 with ethyl acetoacetate derivatives 164 Downloaded by: National University of Singapore. Copyrighted material. 46 and 165, respectively (Scheme 40). R1 = H, R2 = H (90%), 4-Cl (87%), 4-MeO (83%), 3-NO2 (80%) R1 = 4-F, R2 = 4-Cl (79%) R1 = 4-Br, R2 = H (80%) R1 = H, R2 = 4-Br (85%) O 1 Scheme 41 Synthesis of pyranoquinolines 172 and furanoquinolines Cl O T3P in EtOAc Cl R R R1 173 + R2 60 °C, 30–60 min 2 NH2 N R

162 160 161 4.3.8 Thieno[2,3-d]pyrimidin-4-ol 1 2 R = Ph, R = 4-ClC6H4 (94%) 1 2 R = COOEt, R = 4-MeOC6H4 (95%) Thiopyrimidine is a versatile heterocyclic system present R1 = COOEt, R2 = Me (93%) 1 2 in a variety of compounds with broad biological activity R = COOEt, R = CH2Cl (90%) 48 R1 = COPh, R2 = Me (94%) spectra. Poojari et al. reported a one-pot synthesis of thi- 1 2 R = COOEt, R = CH2COOEt (91%) eno[2,3-d]pyrimidin-4-ol derivatives employing T3P R1 = Br, R2 = Ph (96%) (Scheme 42). Scheme 39 Synthesis of polysubstituted quinolines 162

HO zenethiol, o-aminophenol or o-phenylenediamine with O RCOOH (61) N R NH2 T3P in EtOAc carboxylic acids, aldehydes, nitriles or acyl chlorides. 49a Et3N, CH2Cl2 N Wen et al. reported a one-pot synthesis of 1,3-benza- NH2 S S 120 °C, MW zoles employing T3P. The reaction of o-aminobenzeneth- 20 min iol (180; X = S) with p-chlorobenzoic acid in the presence 175 174 of T3P (1.0 equiv) and diisopropylethylamine (1.5 equiv) under microwave irradiation at 100 °C afforded the products 181 within 10 minutes (Scheme 44). Br O O S R = Me O N 100 °C R 10 min S 94% 97% 95% 181 160 °C XH RCOOH N T3P 15 min R F DIPEA Me NH MW 160 °C O MeO N 2 N 180 30 min 182 N S X = O, S, NH N Cl R N H 98% 92% 87% 91% 183

181 R = 4-ClC6H4 (96%), 3-ClC6H4 (90%), 2-ClC6H4 (88%), Scheme 42 Synthesis of thieno[2,3-d]pyrimidin-4-ol derivatives Ph (91%), 4-MeC6H4 (84%), 4-NCC6H4 (95%), 175 4-MeOC6H4 (78%), 4-O2NC6H4 (93%), pyridyl (86%), indolyl (83%), imidazolyl (81%)

182 R = 4-ClC6H4 (95%), Ph (76%), 4-MeC6H4 (73%), The reaction of 5-substituted 2-aminothiophene-3-car- pyridyl (93%), 4-ClC6H4CH2CH2 (91%) boxamides 174 with 4-benzyloxybenzoic acid and T3P 183 R = 4-ClC6H4 (77%), Ph (77%), 4-MeC6H4 (80%), (2.5 equiv) at 120 °C under microwave irradiation for 20 pyridyl (62%), Et (93%), 4-ClC6H4CH2CH2 (90%). minutes gave thieno[2,3-d]pyrimidin-4-ols 175. The reac- Scheme 44 Synthesis of 1,3-benzothiazoles 181, benzoxazoles 182 tions with substituted substrates such as 4-(trifluorometh- and benzimidazoles 183 yl)-1,3-thiazole-2-carboxylic acid and 6-chloro-2-fluoro- 3-methylbenzoic acid were carried out in two steps. Ini- A similar protocol was developed for the synthesis of ben- tially, the amidation was performed at 60 °C for 10 min- zoxazoles and benzimidazoles starting from o-aminophe- utes followed by cyclization which occurred at 120 °C nol (180; X = O) and o-phenylenediamine (180; X = NH). over 20 minutes (Scheme 43). The reaction of o-aminophenol and benzoic acids performed using T3P under microwave irradiation at 160 °C 2

.. S R gave clean conversion into benzoxazoles 182 within 15 H2N O T3P minutes (73–95% yields). In comparison, the reaction of R1COOH P P P 1 174 Et3N HO O O O R H2N o-phenylenediamine and p-chlorobenzoic acid in the pres- 61 O O O O ence of T3P at 100 °C under microwave irradiation gave 9 O the undesired diamide 184 (Figure 12) as the major prod-

H O NH2 uct. NH O

NH 1 NH R MW 2 NH R S 1 2 R OH R S 1 NH R O O O Downloaded by: National University of Singapore. Copyrighted material. R2 S O NH HN 176 H 178 177

H2O OH O Cl Cl NH N 184 R2 R1 S 1 N N R Figure 12 Structure of diamide 184 R2 S 175 179 However, the ratio of formation of benzimidazole and di- Scheme 43 Mechanism for the formation of thieno[2,3-d]pyrimidin- amide was found to be time-dependent and irradiation for 4-ol 30 minutes afforded the benzimidazoles 183 in 62–93% yields. Intramolecular nucleophilic addition followed by 4.3.9 Benzothiazoles, Benzoxazoles and Benzimid- condensation in the presence of T3P, where it acts as wa- azoles ter scavenger, led to the formation of 1,3-benzazoles. 181 General methods available for the preparation of the title and 183 were also accessed through the reaction of alco- heterocycles include the condensation of o-aminoben- hols with o-aminobenzenethiol (180; X = S) and o-phenylenediamine (180; X = NH), respectively, in the

Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1589

OMe presence of T3P and dimethyl sulfoxide under mild con- OMe ditions.49b

MeOOC OMe MeOOC OMe 4.3.10 5,6-Dihydrophenanthridines and 5,6-Dihy- N N H N N drobenzo[c][1,8]naphthyridines H O OMe The Pictet–Spengler reaction of 185 with ethyl glyoxylate 189 190

(186) was carried out at room temperature in the presence MeOOC of T3P under a nitrogen atmosphere to prepare a series of OMe 5,6-dihydrophenanthridines 187 in moderate to good N N H NBoc yields (Scheme 45).50 The presence of T3P in the reaction medium enhances the rate of imine formation. The thus- 191 produced phosphonic acid activates the imine for cycliza- Figure 14 Spiro-compounds formed from cyclic ketones tion to form 187.

O OMe cyanoacetic acid (193) with 2.0 equivalents of T3P in the OMe OHC OEt presence of triethylamine (2.0 equiv) at 120 °C led to 194 (186) 51 T3P in EtOAc (Scheme 46). Several substituted salicyl aldehydes and EtOAc OMe OMe R 2-hydroxyaryl ketones were also treated with 193 to pro- R 25 °C N COOEt vide the corresponding coumarins 194 in 85–98% yield. NH2 H

185 O 187 NC R = 3-Me (93%), 3-F3C (87%), OH 3,5-F (93%), 4-O N (86%), 3-F CO (89%) 2 2 2 3 R 193 R2 T3P in EtOAc O CN Scheme 45 Synthesis of 5,6-dihydrophenanthridines 187 1 (2.0 equiv) R R1 OH Et3N, n-BuOAc 120 °C, 6–10 h O O A similar strategy was followed when the reaction was 192 194 performed between a heterocyclic substrate and a variety R1 = 4-Br, R2 = H (94%) 1 2 of aldehydes and ketones. In contrast to the conditions for R = 4-NO2, R = H (92%) R1 = 3-OMe, R2 = Ph (93%) ethyl glyoxylate, heating at 65 °C for 6–10 hours was es- R1 = 4-F, R2 = Me (92%) sential for carbonyl compounds. Spirophenanthridines Scheme 46 Synthesis of coumarins 194 from cyanoacetic acid 188–191 were also obtained in good yields when cyclic ketones were used (Figure 13 and Figure 14). The protocol was extended to various substituted carbox-

OMe ylic acids such as chloroacetic acid, N-acetylglycine, al- kylsulfonylacetic acids and arylacetic acids to obtain

MeOOC substituted coumarins 195 (Figure 15). The reaction of 2- OMe hydroxyarylcarbonyls with 3,3,3-trifluoropropionic acid R2 N N gave 3-trifluoromethyl-substituted products. In the reac- R1 H tion, T3P in the presence of triethylamine initially forms 188 ester 198 which, upon subsequent heating, undergoes an

R1 = H, R2 = Me (88%), c-Pr (85%), intramolecular Aldol-type condensation to form 195 Downloaded by: National University of Singapore. Copyrighted material. Ph (95%), 2-ClC6H4 (94%), 4-NCC6H4 (97%) R1 = Me, R2 = Me (85%), Ph (90%) (Scheme 47).

Figure 13 5,6-Dihydrobenzo[c][1,8]naphthyridine 188 R

4.3.1 1 Coumarins O O OMe

Coumarin and its derivatives have broad applicability in 195 medicinal chemistry and have been used as fluorescent R = COOMe (94%), CN (92%), Cl (44%), p-Ts (89%), probes as well as in the cosmetics industry. The Perkin re- MeSO2 (94%), Ph (95%), 4-FC6H4 (88%), CF3 (91%) action is the most direct method available for their prepa- Figure 15 Coumarin derivatives ration. Treatment of equimolar quantities of 192 and

O O P CHO O O R P P N O O O N OH O O 196 T3P N Et3N H + O O O R R R HO O O 197 198 199 202

Et3N n-BuOAc, 120 °C N N NH R = O N Me P P P 86% 82% 93% O O O OH R O O O R NH O O H N O O NH N 195 9 Me Me 200 78% 95% 88% 83% Scheme 47 Plausible mechanism for the synthesis of coumarins mediated by T3P Figure 17 Quinoline-substituted pyrazole derivatives 202

4.3.1 2 Imidazo[1,2-a]pyridines 4.4 Oxidation Reactions Imidazo[1,2-a]pyridines 201 were accessed by the reac- The selective oxidation of alcohols to carbonyl com- 54 tion of alcohols, 2-aminopyridines and isocyanides in the pounds is a key transformation that is widely used in the presence of T3P and dimethyl sulfoxide in ethyl acetate production of fine and speciality chemicals. There are (Figure 16).52 Alcohols were thus oxidized to the corre- many reagents for the oxidation of alcohols, and the sponding aldehydes, which in turn formed imines with the Swern oxidation is one such protocol that uses activated amines. Further, T3P allowed for the condensation of the dimethylsulfoxide as an oxidant. In Swern-type oxida- imines and isocyanides to form 201. tions, the activation of dimethyl sulfoxide is violent and exothermic, and successful activation requires low temperatures, usually lower than –20 °C or even as low as R3 N 55 R1 –60 °C. To improve existing strategies, Meudt et al. de- N veloped a modified Swern oxidation in which T3P was HN R2 used in combination with dimethyl sulfoxide as an oxidant 201 (Scheme 48). R2 = t-Bu, Bn, n-pentyl R3 = Cl, F

O T3P in EtOAc O DMSO–EtOAc (1:1) R OH MeO R H R1 = O NC 0 °C to r.t. 66 97 95–96% 82% 85% 78% 94% R = Ph, CH2=CHCH2, Me(CH2)7, Bn Downloaded by: National University of Singapore. Copyrighted material. N Scheme 48 Oxidation of primary alcohols mediated by T3P O N N 2 Br 93% 75% 76% 89% During the reaction, T3P acts as an activator for dimethyl Figure 16 Imidazo[1,2-a]pyridines 201 sulfoxide and in turn activates the alcohol for oxidation to afford the corresponding aldehyde, whereas secondary alcohols gave ketones 155 (Figure 18). The reaction can be 4.3.1 3 Quinoline-Substituted Pyrazole Derivatives carried out at temperatures ranging from –100 °C to A series of quinoline-substituted pyrazole derivatives 202 +120 °C, depending on the substrate. The protocol also were prepared from the corresponding acids and various has the advantage of broad functional group tolerance amines, such as morpholine, diethylamine, dimethyl- (NO2, COOH, Cl, F). amine, cyclopentylamine and cycohexylamine, employ- 53 ing T3P in 82–95% yield (Figure 17). The prepared O molecules showed antibacterial activity against E. coli. R1 R2 155 1 2 R , R = Ph, CH2=CHCH2,CH3(CH2)7, Bn Figure 18 Ketones prepared from secondary alcohols

Synthesis 2013, 45, 1569–1601 © Georg Thieme Verlag Stuttgart · New York REVIEW Propanephosphonic Acid Anhydride 1591

The secondary alcoholic group in the side chain of Boc- The protocol was applied effectively to aromatic, hetero- Thr-OMe (203) was oxidized to produce the correspond- aromatic and aliphatic oximes (Table 11). ing ketone 204 in 97% yield, in the presence of T3P and dimethyl sulfoxide at 0 °C to room temperature without T3P in EtOAc (15 mol%) 55 OH H loss of stereochemistry at the chiral center (Scheme 49). N THF N R2 R1 70 °C 1 2 O R R 84–98% T3P in EtOAc O OH 208 209 DMSO–EtOAc (1:1) OMe OMe BocHN Scheme 51 Catalytic method for the Beckmann rearrangement BocHN 0 °C to r.t. O O 97% 203 204

Scheme 49 Oxidation of (2S,3S)-methyl 2-[(tert-butoxycarbon- Table 11 Amides 209 Prepared from Ketoximes through T3P-Cata- yl)amino]-3-hydroxybutanoate lyzed Beckmann Rearrangement

Amide 209 Yield (%) Amide 209 Yield (%) 4.5 Carbon–Carbon Bond Formation 56 Hermann used T3P, a catalytic amount of N,N-dimeth- H H S N ylaminopyridine and N-ethylmorpholine for the acylation N 93Br 91 of 1,3-cyclohexanedione 205. The reaction was carried O O out in dichloromethane at room temperature, and provided H H the products 207 in moderate yields of 53 and 54% N N 94 90 (Scheme 50). However, the wider utility of T3P in such O O reactions has yet to be established. Cl N OMe H NH N COOH O O O O 94BocN 84 T3P in EtOAc O DMAP, NEM OMe + R R CH2Cl2 OH H H O r.t. O2N N N 205 20653–54% 207 95 91 O O Cl Scheme 50 Synthesis of 2-benzoyl-3-hydroxy-5,5-dimethylcyclo- hex-2-enones 207

4.6 Rearrangement Reactions Here, T3P (15 mol%) reacts with the ketoxime and forms the corresponding nitrilium ion 211 with the expulsion of 4.6.1 Beckmann Rearrangement phosphonate 9. Nucleophilic attack of 9 on 211 leads to For the formation of amide bonds through rearrangement intermediate 212 with a P–O–C bond arrangement, and reactions, not many practical protocols are available but subsequent cleavage of the P–O bond results in the forma- among these, the Beckmann rearrangement is commonly tion of the stable cyclic trimer, T3P (8), with the formation used. This reaction involves the use of a stoichiometric of amide 209 (Scheme 52). quantity of dehydrating reagent, consequently it requires

substantial amounts of solvents, effort and time for the pu- 4.6.2 Curtius Rearrangement Downloaded by: National University of Singapore. Copyrighted material. rification of crude amides. In this context, catalytic methods are gaining popularity. For the rearrangement of a The Curtius rearrangement of acid azides is a widely em- ketoxime 208 to an amide 209, numerous reagents have ployed route for the synthesis of ureas and carbamates. been developed as promoters but their cost, toxicity and The usage of T3P enables the synthesis starting from acids corrosiveness make them less attractive at the industrial to be carried out in a one-pot manner. T3P was used as a level. However, Augustine et al.57 delineated the use of promoter for the formation of acid azides, wherein an acid T3P as a catalytic promoter for the Beckmann rearrange- 61 in the presence of trimethylsilyl azide (1.1 equiv) and ment to ease some of these concerns. Both tetrahydrofu- triethylamine (1.5 equiv) forms an acid azide in situ. Upon ran and N,N-dimethylformamide were effective in heating, the acid azide subsequently undergoes rearrange- affording the amides 209 in good yields (Scheme 51). The ment to the isocyanate, which then couples with the alco- 58 reaction yield was dependent upon the temperature and hol to afford the carbamate 213 or 214 (Scheme 53). The the amount of T3P used. As the temperature and amount yield for all the examples was good to excellent. In this of catalyst were decreased, yields also decreased. The T3P-mediated rearrangement, the reaction rate was shown conversion of acetophenone-oxime into its amide at 70 °C to be faster for substrates having electron-rich substitu- in the presence of 10 mol% of T3P afforded a 92% yield, ents, and slower for those with electron-withdrawing sub- whereas 15 mol% of T3P gave a 98% yield of the product. stituents. The protocol was also extended to prepare benzyl carbamates 214 with aromatic units of different

O O O O O O P P HO O O O P P P O O P

O O O O .. O O O OH OH 8 N P P P 9 N R2 C N R1 R R2 211 R1 R2

208 210 OH O P H O N R2 R2 O O R1 P P O O N O R1 209 8 212 Scheme 52 Reaction mechanism for the Beckmann rearrangement using T3P

substitutions. The reaction was also utilized for the prep- T3P in EtOAc O NMM, NH2OH T3P in EtOAc H aration of tert-butyl carbamates 213. MeCN NMM, R2XH N X R1COOH R1 NHOH R1 R2 reflux O H X = NH, O, S N O t-Bu R 61 215 216 t-BuOH O Scheme 54 Synthesis of ureas and carbamates using T3P as promot- 213 O O O O P P er for the Lossen rearrangement + R OH O O Et3N, TMSN3 P r.t. O 4.7 Synthesis of Drugs on Laboratory and Large 61 8 H BnOH N O Bn Scales R O 214 4.7.1 Denagliptin Tosylate Scheme 53 Curtius rearrangement of carboxylic acids to tert-butyl carbamates 213 and benzyl carbamates 214 Denagliptin tosylate (220) is a dipeptidyl peptidase IV inhibitor that is commercially synthesized (Scheme 55). It is an amide with a nitrile functionality in its core structure. 4.6.3 Lossen Rearrangement Its production was carried out in earlier years employing The Lossen rearrangement59 is the conversion of a hy- HATU or HBTU as coupling agent to join the acid 219 droxamic acid into an isocyanate. It has the advantage of and the nitrile derivative of proline, 218, but the resulting using a stable starting material – a hydroxamic acid – in- product 220 was obtained in 42% yield. In addition, the stead of an acid azide. Reported protocols for hydroxamic relative cost of HATU and HBTU led to the search for an acid synthesis involve the activation of the acid either alternative. In order to develop an economically viable through an acid chloride or a mixed anhydride intermedi- route, the suitabilty of T3P was studied in detail (Scheme

61 Downloaded by: National University of Singapore. Copyrighted material. ate, or involve the use of cyanuric chloride. Aldehydes 55). The use of T3P, as a substitute for HATU and were also converted into the corresponding hydroxamic HBTU, led to 220 in 88% yield with 98% purity (route 1). acids by treatment with hypervalent iodine(III) in the Further improvements in the protocol were made. To presence of hydroxylamine. Recently, Sureshbabu and avoid the two-step process required for the preparation of co-workers60 employed T3P as an acid activator in aceto- the nitrile derivative of proline, coupling followed by de- nitrile to obtain hydroxamic acids 215 under ultrasonica- hydration in an one-pot protocol was envisaged. For the tion and then used as a promoter for the rearrangement of dehydration of amide 221 to nitrile 218, various dehydrat- 215 into isocyanate in the presence of NMM under reflux ing agents were screened, and of them, methanesulfonic conditions. The formed isocyanate was treated with a va- anhydride (Ms2O) afforded the desired product 223 in riety of nucleophiles such as amines, alcohols and thiols 90% yield (route 2). However, the use of methanesulfonic to yield ureas, carbamates and thiocarbamates 216 respec- anhydride is associated with the formation of alkylmeth- tively (Scheme 54). ane sulfonate ester which is known to be a genotoxic im- purity. During the study, it was observed that in the presence of T3P, by raising the temperature and lowering the amount of base, it was possible to carry out both the coupling and

HOOC NHBoc

F F 219 route 1 T3P in EtOAc 88% O i. Boc2O, Py DIPEA NC NH4HCO3 COOH CN p-TsOH N CH2Cl2 219 F F NBoc NH⋅p-TsOH IPA, 60 °C F ii. TFAA, Py NH ⋅p-TsOH i-PrOAc HATU F 2 then p-TsOH⋅H2O 42% DIPEA 220 217 218

F F route 2

219 O O T3P in EtOAc H2N O NC O DIPEA Ms2O, Py N F NH2 EtOAc N EtOAc ⋅ NH p-TsOH F F 50 °C NHBoc 50 °C NHBoc 221 F F

222 223 90% route 3 F

219 O i. T3P in EtOAc O DIPEA NC NH EtOAc, 50 °C F 2 N NH⋅p-TsOH F ii. T3P, 78 °C NHBoc 221 F 223 89%

Scheme 55 Synthesis of denagliptin tosylate (large-scale preparation) the dehydration in one pot. The coupling was carried out 4.7.2 Multidrug-Resistance-Reversal Agents using T3P and then the addition of another equivalent of Multidrug resistance disables many potent anticancer T3P at 78 °C effected dehydration, affording 223 in 89% drugs and is responsible for many of the poor responses to yield with 99% purity (route 3). The protocol was milder cancer chemotherapy. In this context, several disubstitut- especially in view of the large-scale synthesis, as the ear- ed adamantyl derivatives were designed and evaluated in lier protocols were lengthy and required steps like azeo- a p-glycoprotein-dependent multidrug resistance cancer tropic distillation. All the other products produced were cell line by incorporating p-glycoprotein-inhibitor proper- water-soluble and made the product isolation much easier. ties like high hydrophobicity, presence of aromatic rings Clearly, employment of T3P for this dehydration served and protonatable tertiary amines. The ester 224 did not as a better alternative for large-scale synthesis. Both cou- show any reversal activity. Catalytic hydrogenation of the pling as well as cyclodehydration mediated by T3P ester, followed by coupling with an amine employing T3P worked well using a smaller amount of base (DIPEA) un- in the presence of triethylamine at room temperature, re- der an elevated temperature of 50–78 °C. DIPEA was 62 sulted in the amide 225 (Scheme 56). Similarly, ada- Downloaded by: National University of Singapore. Copyrighted material. found to be a better base for tandem coupling and dehy- mantyl derivatives 226 were converted into amides 227 dration processes. This robust route was used to produce (Scheme 57). The thus-obtained amides showed potent re- more than a metric tonne of the drug. versal activity over their ester counterparts.

O O i. H , Pd/C O O O 2 MeOOC N OBn O H ii. T3P, Et3N, RNH2 MeOOC N R CH2Cl2, r.t. H 224 225 yield = 28–70%

OMe OMe N R = N N N N N N N N OMe F CF3 OMe Scheme 56 Synthesis of adamantyl derivative 225

T3P in EtOAc Et N, RNH O H O 3 2 N NaCN MeO OH O R MeO O N N r.t. O O 32–50% MeO MeO 226 227

COOMe O

R = CN CF3 NH2

COOMe Scheme 57 Synthesis of potent multidrug-resistance-reversal agents 227

4.7.3 Somatostatin sst1 Receptors 4.7.4 Prodrugs of SN38 Somatostatin is a peptide hormone generally present in The camptothecin derivative CPT-11, known as irinote- two active forms in biological systems as a tetradecapep- can, is a prodrug approved for the treatment of advanced tide (SRIF14) and a 28-amino acid peptide (SRIF28). Troxler colorectal cancer. The active metabolite of CPT-11 is et al., during their studies on the affinity of ergoline deriv- SN38, which possesses 100- to 1000-fold more potent cy- atives to sst1 receptors, converted the naturally occurring totoxicity than CPT-11 itself. One of the main drawbacks methyl ester of (–)-lysergic acid into 228, a racemic mix- to the use of CPT-11 is its poor solubility in any pharma- ture of a lysergic acid derivative. Treatment of 5-piperi- ceutically acceptable solvent system, and thus it cannot be zin-1-ylbenzo[1,2,5]oxadiazole with racemic 228 used efficiently for systemic applications. To alleviate this mediated by T3P in the presence of pyridine at room tem- limitation, PEGylation of SN38 has been chosen. PEG- perature gave racemic 229 in 82% yield, whereas 1-meth- ylation alters the biodistribution of parent drugs, prolongs yl-6-piperizin-1-ylpyridin-2-one resulted in racemic 230 the circulation time and aids in solubilizing even small in- with 61% yield (Scheme 58).63 The isomers were separat- soluble molecules. PEGylation was carried out through a ed on a chiral stationary phase and subjected to binding prodrug strategy in conjunction with multiarm PEG 232, studies. (–)-ent-229a was 1000-fold more potent and (–)- a 40 kilodalton four-arm-PEG-OH. The active site of each ent-230a showed 400-fold higher affinity than their antipo- arm of multiarm PEG helps to overcome the steric hin- des (+)-229b and (+)-230b to rat and human sst1 receptors. drance and stacking phenomena when drug molecules are close to each other. Thus improves the solubility of the loaded drug molecule.

HN OH

N Br Me

(±)-lysergic acid derivative 228

5-piperazin-1-yl-benzo[1,2,5]oxadiazole 1-methyl-6-piperazin-1-yl-pyridin-2-one Downloaded by: National University of Singapore. Copyrighted material. 82% T3P in EtOAc, 61% Py/DMF, 15 h, r.t.

H O H O HN N N N HN N Me N Br H O N N O Me N N Br H (–)-229a Me (–)-230a

+ +

H O O H HN N N Me HN N N N N N O Br H O N Me N Br H Me (+)-229b (+)-230b

Scheme 58 Synthesis of unnatural enantiomers of the somatostatin receptor subtypes

TBDPSO O TBDPSO N O T3P in EtOAc N DMAP N O N HOOC O-PEG-arm440k O 232 CH2Cl2–DMF O O O O O O r.t. 81% HN

HCl⋅H N 2 O O-PEG-arm440k 231 233

Scheme 59 Synthesis of an SN38 prodrug using a PEG linker

With regard to the synthetic aspect, the preparation of 4.7.6 Phosphodiesterase 9 Inhibitors such prodrugs was initially accomplished using EDC Phosphodiesterase 9 (PDE 9) is one of the three cGMP- which provided 80–89% yields. However, for a multikilo- specific enzymes out of nineteen known PDE-9 isoforms gram-scale preparation, T3P was employed, in the pres- and their synthesis is of significance in drug development. ence of N,N-dimethylaminopyridine, with the solvent In their assembly, cyclodehydration is one of the key system of dichloromethane and N,N-dimethylform- steps, and this has been carried out using a variety of re- amide.64 The use of T3P for N-acylation with four-arm- agents. Among them, selection of T3P for the cyclodehy- PEG-OH gave the receptor 233 in 81% yield after recrys- dration was found to be useful in affording target products tallization using N,N-dimethylformamide and isopropyl 238 in good yields (Scheme 61).66 In this synthesis, both alcohol (Scheme 59). the coupling and the cyclodehydration were carried out in a single pot at room temperature. 4.7.5 Anti-HPV Drug

O 1 R2COOH (61) Human papilloma viruses (HPVs) are small non-envel- R O R1 T3P in EtOAc N N oped DNA viruses that cause a variety of benign, prema- H2N Et3N HN lignant epithelial tumors. Many vaccines have been N N EtOAc R3 N H2N r.t. developed to prevent HPV infection. Of them, tetrahydro- i-Pr i-Pr carbazoles and their derivatives, namely N-[(1R)-6-chloro- 238 237 2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-pyridinecarbox- R1 = H, Me amide (236), were identified as suitable drugs for the treatment of malignant and premalignant tumor cell lines. Initially, acid activation by O-benzotriazole and acid chloride methods were used. However, the reaction using T3P NH NH O N for carboxylic acid activation in the presence of diisopro- 2 N R = O pylethylamine in dichloromethane followed by the addi- O O O tion of amine at 0 °C was clean and very fast. The resultant target product 236 was isolated in 87% yield with 99.5% enantiomeric excess (Scheme 60).65 This ste- Downloaded by: National University of Singapore. Copyrighted material. reoselective synthesis has been scaled up in 200-gallon re- H N NH NH N NH F C N NH actors to produce multiple kilograms of 236 with 99.5% N N 3 O N N enantiomeric purity. HOOC N N COOH O

235 Scheme 61 Synthesis of phosphodiesterase 9 inhibitors

T3P in EtOAc DIPEA Cl Cl O CH2Cl2 4.7.7 Thrombine Inhibitor HN 0 °C N N H N Synthesis of orally active thrombine inhibitors of the D- H NH2 60–87% 236 Phe-Pro-Arg-type requires a safe and toxicity-free cou- 234 99.5% ee pling agent for the amide-bond formation. T3P in ethyl Scheme 60 Asymmetric synthesis of 236 (large-scale preparation) acetate was chosen in the synthesis of these orally active thrombine inhibitors mainly because of the simplicity of both the workup procedure and the isolation of 243 (Scheme 62).67a Schafer and co-workers developed an ef-

© Georg Thieme Verlag Stuttgart · New York Synthesis 2013, 45, 1569–1601 1596 Basavaprabhu et al. REVIEW ficient and convergent process for the synthesis of 244 on three and a half hours. Resolution of the racemic 246 with industrial scale, employing T3P as coupling agent.67b This di-p-toluoyl-L-(–)-tartaric acid [(–)-DTTA] afforded 247 process led to the production of nearly 100 kilograms of in 40 or 41% yield, which led to a 5% improvement rela- thrombine inhibitor 244. tive to the mixed anhydride approach.68

H2N CN 4.7.9 Pharmaceutically Important Cyclic Peptides N (a) T3P in EtOAc Endogenous peptides display a diverse array of biological (1.3 equiv) CN DIPEA interactions, for example as hormones, neurotransmitters OH (4.0 equiv) H N N N or inhibitors. Cyclic peptides often serve as alternative Boc N O 0 °C to r.t. Boc molecules in developing pharmaceutical compounds from O 80% linear peptide lead molecules. However, the synthesis of 239 240 these discrete small cyclic peptides has remained largely

(b) difficult primarily because of sequence-dependent cycli-

CN zation problems or difficulties encountered during reaction workup. N The cyclic pentapeptide cRGDfK (250) acts as a potent N N and selective inhibitor for α β integrin. Previously, HOOC N BocN v 3 H O O N DPPA was used to bring about cyclization of the linear N NH O H O H t COOt-Bu pentapeptide Fmoc-Asp(O Bu)-D-Phe-Lys(Boc)- NH2 Arg(Pbf)-Gly-OH.69a Earlier, cRGDfK was synthesized 243 using a solid-phase approach involving 2-chlorotrityl res- 244 in and Fmoc chemistry,69b to obtain 249 after removal of the Fmoc group and cleavage from the resin. The cycliza-

T3P in EtOAc 95% tion was carried out by employing DPPA as the carboxyl CN (1.0 equiv) DIPEA activator, but owing to its toxic nature, Liu and co- H (4.0 equiv) N N 69c N + BocN COOH workers employed an alternative – the relatively non- H CH2Cl2 O 0 °C to r.t. toxic T3P - for the process to obtain cRGDfK (250) in COOt-Bu 97% yield (Scheme 64). The product isolation was easy and for the final purification, silica gel chromatography 241 242 was sufficient. After the removal of other protections in- Scheme 62 Synthesis of active intermediates in the preparation of cluding Pbf, Boc, and t-Bu, the final cRGDfK was ob- thrombine inhibitor 244 tained in 82% yield, a yield that was significantly higher than the previously reported 44%. 4.7.8 Norepinephrine Reuptake Inhibitor Cycloaspeptide E, a member of the cycloaspeptide family, was extracted from Penicillia and Trichothecium strains Norepinephrine reuptake inhibitors such as 248, contain- of fungi. It is the first member of the family found to ex- ing a 2-substituted morpholine moiety, have been used for hibit insecticidal activity. The linear peptide fragment 251 the treatment of depression and thus these compounds are was synthesized through an Fmoc-amino acid chloride marketed worldwide as drugs. The initial attempt to syn- method. When the macrocyclization was carried out using thesize the key intermediate 247 through an acid chloride DPPA, 252 was obtained in low yields (10–15%) and led method was abandoned owing to the low solubility. The to the formation of major byproduct 253 through azide at- Downloaded by: National University of Singapore. Copyrighted material. mixed anhydride method using isobutyl chloroformate for tack of DPPA on the activated acid group. Lewer et al.70 the coupling of acid 245 and morpholine yielded good re- performed the same macrocyclization with T3P in the sults and the same was further used for industrial-scale presence of triethylamine and catalytic N,N-dimethylami- synthesis. However, in further studies, the usage of T3P nopyridine in anhydrous dichloromethane at room tem- was screened as the coupling agent (Scheme 63). The cou- perature. The desired product 252 was thus obtained in pling, leading to 246, was found to be complete within 67% yield (Scheme 65).

O H O O O O H H H OH O O O N N i. T3P, DIPEA N THF O (–)-DTTA O O HCl N N N ii. morpholine 2-PrOH H 40% (–)-DTTA

248 245 246 247

Scheme 63 Synthesis of norepinephrine reuptake inhibitor 248

O O

t-BuO O HO O H2N i. 50% T3P in EtOAc O HN NH Et3N–DMAP NH HOOC CH2Cl2, r.t. NH O HN O ii. H2O–TFA (1:19) NH NH O O N N H H HN O HN O PbfHN NHBoc H2N NH2 NH 249 NH 250 Scheme 64 Synthesis of cRGDfK (250)

Me N HN

O O HN O NH N O O OH Me HN H N R O N HN O Me cycloaspeptide E (252) T3P in EtOAc O O NH Me HN O Et N, DMAP 10–15% DPPA 3 HN O CH Cl DMF N 2 2 NH Me O r.t. + N r.t. O O 67% O

HN NH2 H R N 251 R O Me R = H, OH, OTf cycloaspeptide E (252) NH Me HN O N O O

R major byproduct 253

Scheme 65 Synthesis of cycloaspeptide E (252)

5 Recent Applications The protocol was advantageous as it tolerated acid-sensitive functionalities. Aromatic aldehydes with electron- Downloaded by: National University of Singapore. Copyrighted material. donating or -withdrawing substituents, and aliphatic and 5.1 Conversion of Aldehydes and Ketones into sterically hindered aldehydes were converted into the cor- Acetals and Thioacetals responding acetals or thioacetals 255–257. The protocol The protection of aldehydes and ketones is an important was general with respect to primary, secondary and tertia- component of multistep synthesis endeavors, and this is ry alcohols, where 1,2-diols gave 1,3-dioxolanes, 1,3-di- often carried out through acetalization or thioacetaliza- ols gave 1,3-dioxanes, and 1,3-dithiols gave 1,3-dithianes. tion. Several Bronsted and Lewis acids have been used to At first, the reaction of an aldehyde with an alcohol em- accelerate acetal formation. A chemoselective reaction of ploying T3P results in the formation of oxocarbenium ion aldehydes 254 and alcohols or thiols using a catalytic 259 by ring opening of the cyclic trimer. Later, the nucleo- amount of T3P (10 mol%) under mild conditions to pro- philic attack of another alcohol molecule on the oxocarbe- duce acetals or thioacetals (Scheme 66) was developed.71 nium ion gives the acetal 255. The phosphonate thus produced regenerates the catalyst through cyclization (Scheme 67).

T3P in EtOAc the corresponding methyl ketones (Scheme 68). In all (10 mol%) R2 CHO X cases, the formation of the acetal intermediate 261 was R2OH or R2SH R2 (2.2 equiv) X found to be more favored than that of the corresponding EtOAc, r.t. ketal 262 by several kilocalories per mole, owing to the R1 R1 steric crowding offered by the substituents. Because of the 254 255–257 difference in transition-state energies, aldehydes acetalize 255: X = O, R2 = Me, R1 = Cl (94%), preferentially even in the presence of a keto group. NO2 (92%), CN (92%), COOH (93%), Me O 1 2 256: X = O, R = p-NO2, R = ethanol (93%), H P isopropanol (91%), O O 1,2-ethanediol (98%), .. R O O R MeOH O P P O pinacol (91%), .. O HOMe 1,3-propanediol (95%), Me Me 1-phenyl-1,2-ethanediol (89%) (MCPA) 1,2-propanediol (93%), 260 1,2-cyclohexanediol (94%); 1 2 X = S, R = p-NO2, R = 1,3-propanedithiol (95%). 257: X = O, R1 = p-COMe, R2 = 1,3-propanedithiol (96%), 2-ethanedithiol (95%), pinacol (91%); O O O X = S, R1 = p-COMe, R2 = 1,3-propanedithiol (96%), H O O O O O O OH O O O OH MeO P P P 1,2-ethanedithiol (94%), MeO P P P thiophenol (95%) R Me Me Me R Me Me Me 262 Scheme 66 Acetalization and thioacetalization of aldehydes cata- 261 lyzed by T3P TS energy = –13.18 Kcal/mol TS energy = –4.39 Kcal/mol

Scheme 68 Chemoselectivity reaction of aldehydes versus ketones using MCPA

5.2 Linear and Cyclic Thiophenamides O P R1 O O HO.. The synthesis of thiophene oligoamides from the corre- H (66) H O O O O O O O O P P P P P sponding amines 263 and carboxylic acids 264 was O O O.. O 1 R2 R R2 achieved in the presence of T3P and triethylamine using ultrasonication (Scheme 69).72 Linear oligomer 266 was 8 97 258 obtained in 68% yield when EDC was employed, whereas T3P under ultrasonication afforded the product in 91% O O O – OH O O O .. yield. Macrocyclization of the tetramer using T3P gave HO P P P HO R1 the cyclic thiophene oligoamide 267 in 46% yield. O H R1 R2 5.3 Hepatoselective Glucokinase Activator 259 Glucokinase is an enzyme in the liver and pancreas that regulates glucose metabolism, and the compounds that ac- H tivate this enzyme are promising therapies for type II dia- R1 O betes. In an attempt to develop a robust process for the 1

R multikilogram synthesis of hepatoselective glukokinase Downloaded by: National University of Singapore. Copyrighted material. R2 O activator 270, various coupling reagents were employed. 255 Reactions using DCC and HATU conditions provided 270 Scheme 67 Reaction pathway for T3P-mediated acetalization in the greatest optical purity, but the byproducts obtained were difficult to remove. On the other hand, EDC, CDI, 2- chloro-4,6-dimethoxy-1,3,5-triazine and DEPBT caused The chemoselectivity of the reaction was elucidated by reacemization, and with the former reagent, the reaction the transition-state energies of aldehydes and ketones was sluggish, too. The protocol employing T3P in the based on quantum mechanical calculations using density 71 presence of pyridine and 2,6-lutidine gave good results in functional theory. affording the target molecule.6,73 However, on scale-up, The less flexible methyl analogue of T3P, methylcyclo- T3P in the presence of pyridine and N,N-dimethylamino- phosphonic anhydride (MCPA; 260), was employed to pyridine at 0 °C provided 270 in 84% yield with achiral compare the energies of intermediates 261 and 262 with purity of 99.5% after recrystallization (Scheme 70). those of the starting materials for both the aldehydes and

t-BuOOC H COOt-Bu COOt-Bu T3P in EtOAc N Et3N, CH2Cl2 COOt-Bu MeOOC + HOOC NH ))))) S O S S 2 S NHCbz 98% MeOOC NHCbz 263 264 265

t-BuOOC T3P in EtOAc H N Et3N, CH2Cl2 COOt-Bu ))))) 91% S O S t NH COOt-Bu COO Bu COOt-Bu hydrolysis and Pd/C, H2 O O O O 'macrocyclization' HN NHCbz T3P in EtOAc S N S N S H H 2 S O S Et3N, CH2Cl2 MeOOC t-BuOOC ))))) 46% N 266 H COOt-Bu 267

Scheme 69 Synthesis of linear and cyclic thiophenamides

to expand. In our opinion, the potential of the reagent will COOBn be tested to its limit in the years to come. COOBn T3P in EtOAc O N COOH Py, DMAP EtOAc N N N + 0 °C H Acknowledgement 84% N N NH2 N V.V.S. is grateful to the late Prof. K. M. Sivanandaiah, Bangalore CF3 CF3 University, for his guidance in the initial stages establishing the 268 269 270 peptide research group at Central College, Bangalore (CCB) and to the late Prof. B. S. Sheshadri for his untiring support in providing Scheme 70 Synthesis of hepatoselective glucokinase activator 270 laboratory space at CCB in 1998. He is ever thankful to Drs. H. N. Gopi and K. Ananda for their toiling work in establishing the group T3P proved efficient for the coupling of racemization- during its infancy. He is grateful to Professor M. S. Thimappa and prone carboxylic acids 268 with relatively non-nucleo- Dr. N. Prabhudev, formerly Vice-Chancellors of Bangalore Univer- philic amines 269 on a large scale as well. This T3P-cata- sity, for extending academic support for the sustenance of the research group at CCB. We thank Professor Emeritus T. Shiori, lyzed bond formation provided more than 140 kilograms Nagoya City University, Japan, for useful discussions which in- of amide over five batches in 84–88% of yield. spired us to use T3P in our laboratory. The Department of Science and Technology, Council of Scientific and Industrial Research, Department of Biotechnology, University Grants Commission, 6 Conclusion Government of India, New Delhi and Board of Research in Nuclear Sciences, Mumbai are thanked for generous financial support. In the last few years, there has been an upsurge of interest in T3P as a versatile reagent for synthesis. This stems References from the fact that T3P is useful in mediating a plethora of chemical transformations under mild and easily scalable (1) (a) Wissmann, H.; Kleiner, H.-J. Angew. Chem. 1980, 92,

133. (b) Wissmann, H. Phosphorus Sulfur Relat. Elem. Downloaded by: National University of Singapore. Copyrighted material. conditions that are key to preparing several classes of 1987, 30, 645. (c) Escher, R.; Buning, P. Angew. Chem. Int. compounds, of which many are of biological relevance. Ed. 1986, 25, 277. (d) Wissmann, H.; König, W.; Geiger, R. With its easy product isolation, the protocol employing In Peptides: Structure and Funciton. Proceedings of the 8th T3P offers several practical and experimental benefits to American Peptide Symposium; Hruby, V. J.; Rich, D. H., the synthetic chemist. Multistep and one-pot protocols can Eds.; Pierce Chem. Co: Rockford (IL, USA), 1983, 111. be carried out effectively when mediated by T3P. Also, (2) (a) Wehner, M.; Kirschbaum, B.; Deutscher, L.; Wagner, H. J.; Hoessl, H. PCT Int. Appl. WO 2005014604, 2005; Chem. the reagent can be applied to the large-scale preparation of Abstr. 2005, 142, 198208. (b) Schwarz, M. Synlett 2000, several commercially produced compounds; for instance, 1369. (c) Llanes García, A. L. Synlett 2007, 1328. for a metric-tonne preparation of denagliptin tosylate, a (d) Coupling Agent T3P—The Water Scavenger dipeptidyl peptidase IV inhibitor for the treatment of type http://www.euticals.com./attachments/082_EUTICALS_ II diabetes. T3P-Coupling-Agents_2012_final_web.pdf (e) Koch, P.; Vedder, C.; Schaffer, T. Chim. Oggi/Chem. Today 2008, 26 With regard to the research in synthetic chemistry, the (Suppl. 4), 6. quest for new methods and reagents that excel in selectiv- (3) (a) Lutz, J.; Musiol, H.-J.; Moroder, L. In Houben-Weyl: ity, mildness and efficacy is a never-ending endeavor. In Synthesis of Peptides and Peptidomimetics; Vol. E22a; this quest, T3P as a reagent will continue to thrive with Goodman, M.; Felix, A.; Moroder, L.; Toniolo, C., Eds.; wider acceptability as its sphere of applications continues Georg Thieme: Stuttgart, 2004, 427. (b) Sewald, N.; Jakubke, H. D. In Peptides: Chemistry and Biology; Wiley-

VCH: Weinheim, 2002. (c) El-Faham, A.; Albericio, F. (21) Wedel, M.; Walter, A.; Montforts, F.-P. Eur. J. Org. Chem. Chem. Rev. 2011, 111, 6557. 2001, 1681. (4) Hughes, A. In Amino Acids, Peptides and Proteins in (22) (a) Newcomb, M. Tetrahedron 1993, 49, 1151. (b) Hartung, Organic Chemistry: Protection Reactions Combinatorial J.; Hiller, M.; Schwarz, M.; Svobola, I.; Fuess, H. Liebigs and Medicinal Chemistry; Vol. 4; Sureshbabu, V. V.; Ann. 1996, 157. (c) Barton, D. H. R.; Blundell, P.; Narendra, N., Eds.; Wiley-VCH: Weinheim, 2011, 1–96. Jaszberenyi, J. C. J. Am. Chem. Soc. 1991, 113, 6933. (5) Hiebl, J.; Alberts, D. P.; Banyard, A. F.; Baresch, K.; (d) Hartung, J.; Schwarz, M. Synlett 2000, 371. Baumgartner, H.; Burnweiser, I.; Bhatnagar, P. K.; Blanka, (23) (a) Patterson, J. E.; Ollman, I. R.; Cravatt, B. F.; Boger, D. M.; Bodenteich, M.; Chen, T.; Esch, P. M.; Kollmann, H.; L.; Wong, C.-H.; Lerner, R. A. J. Am. Chem. Soc. 1996, 118, Lantos, I.; Leitner, K.; Mayrhofer, G.; Patel, R.; Rio, A.; 5938. (b) Vasanthakumar, G. R.; Sureshbabu, V. V. Rovenzsky, F.; Stevenson, D.; Tubman, K. D.; Undheim, K.; Tetrahedron Lett. 2003, 44, 4099. (c) Ech-Chahad, A.; Weihtrager, H.; Welz, W.; Winkler, K. J. Pept. Res. 1999, Minassi, A.; Berton, L.; Appendino, G. Tetrahedron Lett. 54, 54. 2005, 46, 5113. (6) Dunetz, J. R.; Xiang, Y.; Baldwin, A.; Ringling, J. Org. Lett. (24) Meudt, A.; Boehm, C. PCT Int. Appl. WO 2007006465, 2011, 13, 5048. 2007; Chem. Abstr. 2007, 146, 17230. (7) (a) Wenger, R. M. Helv. Chim. Acta 1984, 67, 502. (25) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, (b) Klose, J.; Bienert, M.; Mollenkopf, C.; Wehle, D.; 3815. (b) Balasubhramanium, S.; Aidhen, I. S. Synthesis Zhang, C.-W.; Carpino, L. A.; Henklein, P. Chem. Commun. 2008, 3707. 1999, 1847. (26) Sureshbabu, V. V.; Hemantha, H. P. ARKIVOC 2008, (ii), (8) (a) Basavaprabhu, ; Narendra, N.; Lamani, R. S.; 243. Sureshbabu, V. V. Tetrahedron Lett. 2010, 51, 3002. (27) Fish, P. V.; Deur, C.; Gan, X.; Greene, K.; Hoople, D.; (b) Sureshbabu, V. V.; Ananda, K.; Vasanthakumar, G. R. MacKenny, M.; Para, K. S.; Reeves, K.; Ryckmans, T.; Stiff, J. Chem. Soc., Perkin Trans. 1 2000, 4328. (c) Katritzky, A. C.; Stobie, A.; Wakenhut, F.; Whitlock, G. A. Bioorg. Med. R.; Widyan, K.; Kirichnko, K. J. Org. Chem. 2007, 72, 5802. Chem. Lett. 2008, 18, 2562. (d) Patil, B. S.; Vasanthakumar, G. R.; Sureshbabu, V. V. (28) Burkhart, F.; Hoffmann, M.; Kessler, H. Angew. Chem., Int. J. Org. Chem. 2003, 68, 7274. Ed. Engl. 1997, 36, 1191. (9) (a) Hemantha, H. P.; Narendra, N.; Sureshbabu, V. V. (29) Wang, D.; Nugent, W. A. J. Org. Chem. 2007, 72, 7307. Tetrahedron 2012, 68, 9491. (b) Rao, Y.; Nagorny, P.; (30) Sharanabai, K. M.; Nagendra, G.; Vishwanatha, T. M. Hayashida, J.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, Sureshbabu V. V. Tetrahedron Lett. 2013, 54, 478 . 6684. (c) Wu, X.; Stockdill, J. L.; Wang, P.; Danishefsky, S. (31) Meudt, A.; Scherer, S.; Nerdinger, S. PCT Int. Appl. WO J. J. Am. Chem. Soc. 2010, 132, 4098. (d) Raibaut, L.; 2005070879, 2005; Chem. Abstr. 2005, 143, 172649. Ollivier, N.; Melnyk, O. Chem. Soc. Rev. 2012, 41, 7001. (32) Augustine, J. K.; Atta, R. N.; Ramappa, B. K.; Boodappa, C. (e) Kent, S. B. H. Chem. Soc. Rev. 2009, 38, 338. Synlett 2009, 3378. (10) (a) Madhu, C.; Basavaprabhu, ; Vishwanatha, T. M.; (33) Meudt, A.; Scherer, S.; Nerdinger, S. PCT Int. Appl. WO Sureshbabu, V. V. Tetrahedron Lett. 2012, 53, 1405. 2005073456, 2005; Chem. Abstr. 2005, 144, 13496. (b) Crich, D.; Sasaki, K.; Rahaman, Md. Y.; Bowers, A. A. (34) Jung, T. S.; Malatin, K.; Teall, M. PCT Int. Appl. WO J. Org. Chem. 2009, 74, 3886 . 2004103234, 2004; Chem. Abstr. 2004, 143, 64324. (11) Wang, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, (35) Meudt, A.; Scherer, S.; Böhm, C. PCT Int. Appl. WO 17045. 2005123632, 2005; Chem. Abstr. 2005, 144, 69544. (12) Nagendra, G.; Madhu, C.; Vishwanatha, T. M.; Sureshbabu, (36) Augustine, J. K.; Vairaperumal, V.; Narasimhan, S.; V. V. Tetrahedron Lett. 2012, 53, 5059. Alagarsamy, P.; Radhakrishnan, A. Tetrahedron 2009, 65, (13) (a) Benotoin, N. L. Chemistry of peptide synthesis; Taylor 9989. and Francis: New York, 2006, 197–242. (b) Wissmann, H.; (37) Crawforth, J. M.; Paoletti, M. Tetrahedron Lett. 2009, 50, König, W.; Teetz, V.; Geiger, R. Peptides: Proceedings of 4916. the 16th European Peptide Symposium; Brunfeldt, K., Ed.; (38) Crichfield, K. S.; Hart, J. E.; Lampert, J. T.; Vaid, R. K. Scriptor: Copenhagen, 1980, 174. Synth. Commun. 2000, 30, 3737. (14) (a) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, (39) Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999, G. R.; Leazer, J. L.; Linderman, R. J. Jr; Lorenz, K.; Manley, 1799.

J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green (40) Zumpe, F. L.; Melanie, F.; Schmitz, K.; Lender, A. Downloaded by: National University of Singapore. Copyrighted material. Chem. 2007, 9, 411. (b) Allen, C. L.; Williams, J. M. J. Tetrahedron Lett. 2007, 48, 1421. Chem. Soc. Rev. 2011, 3405. (c) Han, S.-Y.; Kim, Y.-A. (41) Holla, W.; Napierski, B.; Rebenstock, H.-P. Ger. Offen. DE Tetrahedron 2004, 60, 2447. (d) Montalbetti, C. A. G. N.; 19802969, 1999; Chem. Abstr. 1999, 131, 131507. Falque, V. Tetrahedron 2005, 61, 10827. (42) Desroses, M.; Wiekowski, K.; Stevens, M.; Odell, L. R. (15) Glauder, J. Speciality Chemicals Magazine 2004, 24, 30. Tetrahedron Lett. 2011, 52, 4417. (16) Bialy, L.; Diaz-Mochon, J. J.; Specker, E.; Keinicke, L.; (43) Prasanna, T. S. R.; Mohan Raju, K. J. Korean Chem. Soc. Bradley, M. Tetrahedron 2005, 61, 8295. 2012, 56, 74. (17) Schmidt, J. P.; Beltron-Rodil, S.; Cox, R. J.; McAllister, G. (44) Singh, S. P.; Parmar, S. S.; Raman, K.; Stenberg, V. I. Chem. D.; Reid, M.; Taylor, R. J. K. Org. Lett. 2007, 9, 4041. Rev. 1981, 81, 175. (18) Helal, C. J.; Kang, Z.; Lucas, J. C.; Gant, T.; Ahlijanian, M. (45) Sharath Kumar, K. S.; Swaroop, T. R.; Harsha, K. B.; K.; Schachter, J. B.; Richter, K. E. G.; Cook, J. M.; Menniti, Narasimhamurthy, K. H.; Rangappa, K. S. Tetrahedron Lett. F. S.; Kelly, K.; Mente, S.; Pandit, J.; Hosea, N. Bioorg. 2012, 53, 5619. Med. Chem. Lett. 2009, 19, 5703. (46) Jida, M.; Deprez, B. New J. Chem. 2012, 36, 869. (19) Appendino, G.; Minassi, A.; Berton, L.; Moriello, A. S.; (47) Prasanna, T. S. R.; Mohan, R. E-J. Chem. 2011, 8, 420. Cascio, M. G.; Petrocellis, L. D.; Marzo, V. D. J. Med. (48) Poojari, S.; Naik, P. P.; Krishnamurthy, G. Tetrahedron Lett. Chem. 2006, 49, 2333. 2012, 53, 4639. (20) Edwards, M. G.; Kenworthy, M. N.; Kitson, R. R. A.; Scott, (49) (a) Wen, X.; Bakali, J. E.; Deprez-Poulian, R.; Deprez, B. M. S.; Taylor, R. J. K. Angew. Chem. Int. Ed. 2008, 47, 1935. Tetrahedron Lett. 2012, 53, 2440. (b) Raghavendra, G. M.;

Ramesha, A. B.; Revanna, C. N.; Nandeesh, K. N.; Greeneberger, L. M.; Horak, I. D. Bioconjugate Chem. 2008, Mantelingu, K.; Rangappa, K. S. Tetrahedron Lett. 2011, 52, 19, 849. 5571. (65) Boggs, S. D.; Cobb, J. D.; Gudmundsson, K. S.; Jones, L. A.; (50) Augustine, A. K.; Bombrun, A.; Algarsamy, P.; Jothi, A. Matsuoka, R. T.; Miller, A.; Patterson, D. E.; Samano, V.; Tetrahedron Lett. 2012, 53, 6280. Trone, M. D.; Xie, S.; Zhuo, X. Org. Process Res. Dev. (51) Augustine, A. K.; Bombrun, A.; Ramappa, B.; Boodappa, C. 2007, 11, 539. Tetrahedron Lett. 2012, 53, 4422. (66) Deninno, M. P.; Andrews, M.; Bell, A. S.; Chen, Y.; Eller- (52) Ramesha, A. B.; Raghavendra, G. H.; Nandeesh, K. N.; Zarbo, C.; Eshelby, N.; Etienne, J. B.; Moore, D. E.; Palmer, Rangappa, K. S.; Mantelingu, K. Tetrahedron Lett. 2013, 54, M. J.; Visser, M. S.; Yu, L. J.; Zavadoski, W. J.; Gibbs, E. 95. M. Bioorg. Med. Chem. Lett. 2009, 19, 2537. (53) Chandrakantha, B.; Isloor, A. M.; Peethambar, S. K.; Shetty, (67) (a) Harrison, T.; Owens, A. P.; Sadowski, S.; Cascieri, M. A. P. Pharm. Chem. 2012, 4, 1723. Bioorg. Med. Chem. Lett. 2003, 13, 2341. (b) Harald, B.; (54) Barnes, I.; Hjorth, J.; Mihalopoulos, N. Chem. Rev. 2006, Gerd, B.; Udo, E. W. L.; Helmut, M.; Thomas, P.; Bernd, S.; 106, 940. Werner, S.; Thomas, Z. Synthesis 2004, 2367. (55) Meudt, A.; Scherer, S.; Böhm, C. PCT Int. Appl. WO (68) Kopach, M. E.; Singh, U. K.; Kobierski, M. E.; Trankle, W. 2005102978, 2005; Chem. Abstr. 2005, 143, 440908. G.; Murray, M. M.; Pietz, M. A.; Frost, M. B.; Stephenson, (56) Hermann, S. Ger. Offen. DE 10063493, 2002; Chem. Abstr. G. A. Org. Process Res. Dev. 2009, 13, 209. 2002, 137, 47003. (69) (a) Haubner, R.; Gratius, R.; Diefenbach, B.; Goodman, S. (57) Augustine, J. K.; Kumar, R.; Bombrun, A.; Mandal, A. B. L.; Jonczyk, A.; Kessler, H. J. Am. Chem. Soc. 1996, 118, Tetrahedron Lett. 2011, 52, 1074. 7461. (b) Dechantsreiter, M. A.; Planker, E.; Matha, B.; (58) Augustine, J. K.; Bombrun, A.; Mandal, A. B.; Alagarsamy, Lohof, E.; Holzeman, G.; Jonczyk, A.; Goodman, S. L.; P.; Atta, R. N.; Selvam, P. Synthesis 2011, 1477. Kessler, H. J. Med. Chem. 1999, 42, 3033. (c) Dai, X.; Su, (59) Ozaki, S. Chem. Rev. 1972, 72, 457. Z.; Liu, J. O. Tetrahedron Lett. 2000, 41, 6295. (60) Vasantha, B.; Hemantha, H. P.; Sureshbabu, V. V. Synthesis (70) Lewer, P.; Graupner, P. R.; Hahn, D. R.; Karr, L. L.; 2010, 2990. Dubelbeis, D. O.; Lira, J. M.; Anzeveno, P. B.; Fields, S. C.; (61) Patterson, D. E.; Powers, J. D.; LeBlanc, M.; Sharkey, T.; Gilbert, J. R.; Pearce, C. J. Nat. Prod. 2006, 69, 1506. Boehler, E.; Irdam, E.; Osterhout, M. H. Org. Process Res. (71) Augustine, J. K.; Bombrum, A.; Sauer, W. H. B.; Dev. 2009, 13, 900. Vijaykumar, P. Tetrahedron Lett. 2012, 53, 5030. (62) Min, K. H.; Xia, Y.; Kim, E. K.; Jin, Y.; Kaur, N.; Kim, E. (72) Ngo, T. H.; Brendt, H.; Lentz, D.; Reissig, H.-U. J. Org. S.; Kim, D. K.; Jung, H. Y.; Choi, Y.; Park, M.; Min, Y. K.; Chem. 2012, 77, 9676. Lee, K.; Lee, K. Bioorg. Med. Chem. Lett. 2009, 19, 5376. (73) Dunetz, J. R.; Berliner, M. A.; Xiang, Y.; Houck, T. L.; (63) Troxler, T.; Enz, A.; Hoyer, D.; Langenegger, D.; Neumann, Salingue, F. H.; Chao, W.; Yuandong, C.; Shenghua, W.; P.; Pfaffi, P.; Schoffter, P.; Hurth, K. Bioorg. Med. Chem. Huang, Y.; Farrand, D.; Boucher, S. J.; Damon, D. B.; Lett. 2008, 18, 979. Makowski, T. W.; Barrila, M. T.; Chen, R.; Martinez, I. Org. (64) Zhao, H.; Rubio, B.; Sapra, P.; Wu, D.; Reddy, P.; Sai, P.; Process Res. Dev. 2012, 16, 1635. Martnez, A.; Gao, Y.; Lozanguiz, Y.; Longley, C.; Downloaded by: National University of Singapore. Copyrighted material.