Application of multicomponent reactions in the total synthesis of natural peptides

Multicomponent reactions (MCRs) have been widely applied for the synthesis of biologically active molecules with high complexity and diversity. Nowadays, total synthesis of natural peptides, due to their multifarious application areas, has attracted much attention of organic chemists. MCRs are a powerful and efficient method for the production of natural peptides in a limited number of steps. This review presents an overview on application of multicomponent reactions as a key step in the synthesis of natural peptides


Introduction
Short chains of amino acid monomers which are linked together by peptide bonds (-CONH-), form the proteins and peptides. 1,2Since the 1920s and particularly since the commercial introduction of insulin and thyroid hormones, many peptides have been employed as drugs. 3,4 lthough peptides often have lower bioavailability and metabolic stability than antibodies and proteins, they also have beneficial properties such as being less immunogenic, of greater stability, of lower manufacturing costs and better penetration into organs and tissues. 5][8] Advances in this regard are due to discovery of solid-supported synthesis 9,10 and the development of reagents and methods for direct amide formation. 7Nevertheless, novel methods for the rapid production of these biopolymers are constantly being explored.Numerous strategies have been developed in order to facilitate the synthesis of complex natural products.One avenue in emulating nature's efficiency would consist of merging compatible single bond forming processes to allow multiple bond forming events to occur between several substrates, a concept generally termed multicomponent reactions (MCRs).The development of multicomponent reactions has created an emerging concept in this context.MCRs are described, regardless of their mechanistic nature, as a "one-pot" transformations that involve the reaction of at least three components to generate a single product.The significant features of these reactions included speed, atom economy, diversity, step efficiency, and environmental friendliness.MCRs have a high potential for the synthesis of diversityoriented combinatorial libraries to accomplish the preparation of highly complex natural products and biological targets 7,8,[11][12][13] In this paper, and in continuation of our studies on multi-component reactions, [11][12][13][14][15][16][17][18][19][20] we present an overview on the total synthesis of natural peptides via multicomponent reactions.

Syntheses based on the Ugi reaction
The Ugi reaction, discovered by Ivar Karl Ugi in 1959, is a highly efficient method in which a primary amine, an aldehyde, an isocyanide, and a carboxylic acid, react in a one pot procedure to furnish an N-substituted αamino acid amide backbone. 21s an example in the area of peptide chemistry, the Ugi reaction was used as main step for the synthesis of ustiloxin D (8): Joullié and co-workers reported in 2002 the first synthesis of this 13-membered cyclic antimitotic peptidefrom readily available D-serine and an aryl fluoride as the starting materials.The total synthesis of compound 8 was also performed in 2015 by Hutton et al. in several steps respectively via a) aldol reaction, b) Tsuji-Trost asymmetric allylic alkylation (AAA) reaction, c) Ugi reaction with ammonia and d) macrocyclization as the key steps (Scheme 1). 22This antimitotic agent was originally isolated in 1992 by Iwasaki and co-workers from the water extract of false smut balls found on the panicles of rice plants, a plant disease caused by the fungus Ustilaginoidea virens. 23Biological screening of ustiloxin D (8) exhibited potent inhibition for microtubule assembly by interfering with tubulin polymerization at low micromolar concentrations. 24,25 he synthetic route started with the β-OH DOPA derivative 3 which was in turn obtained in several steps from the reaction of oxazole 1 with benzaldehyde 2 through the aldol-type reaction. 26Then, compound 3 was converted in several steps into the corresponding aldehyde 4 which was subjected to Ugi reaction with benzyl isocyanoacetate 5, N-Boc-valine 6, and NH3 to furnish a 1:1 mixture of inseparable epimers of tripeptide-DOPA adduct 7 in high yield.Finally, deprotection and macrolactamization of compound 7 followed by hydrogenolysis of the benzylic protecting groups of the corresponding macrocycle furnished the desired natural product 8.During macrocyclization of mixture of epimers 7 deprotected with EDC, only the expected (αS)-isomer undergoes macrolactamization, whereas the (αR)-isomer undergoes oligomerization, providing a way to separate the epimeric products in this step.Also based on the Ugi reaction, the total syntheses of pacidamycin D (9) and its 3'-hydroxyl analogue 10 were reported via a copper-catalyzed C-N cross-coupling (Scheme 2). 27The pacidamycins belong to the class of naturally occurring nucleosidyl-peptide antibiotics which were originally isolated from the fermentation broth of Streptomyces coeleorubidus AB 1183F-64. 28These products inhibited phospho-MurNAcpentapeptidetransferase (MraY) and showed highly specific activity with Pseudomonas aeruginosa.Scheme 2. The structures of pacidamycin D 9 and its 3'-hydroxyl analogue 10.
In another study, based on the Ugi reaction, an efficient and convergent pathway for the secondgeneration total synthesis of 3'-hydroxypacidamycin D 10 was reported by Ichikawa's group (Scheme 3). 29iological evaluation showed that the presence of OH group at the 3'-position in product 10 does not have any impact on either MraY inhibition or whole-cell antibacterial activity.The synthesis of antibiotic 10 was achieved through key intermediate 16.The Ugi reaction of the urea dipeptide 11, 2,4-dimethoxybenzylamine 12, the 2-N-methylaminopropionaldehyde derivative 13 and the unsaturated isonitrile derivative of uridine 14 provided the diastereomers 15 in 30% yield and 16 in 33% yield.The desired isomer 16, after separation, was converted into compound 10 in several steps.
The Ugi reaction has been also applied by Ichikawa et al. in 2010 for the total synthesis of (-)-muraymycin D2 and its epimer (Scheme 4). 30Muraymycins (MRY) belong to the class of naturally occurring 6'-N-alkyl-5'-α-O-aminoribosyl-C-glycyluridine antibiotics which possess a unique core structure.McDonald et al. first isolated them from the culture broth of Streptomyces sp in 2002. 31These natural products showed in vitro antimicrobial activity against Gram-positive bacteria such as Staphylococcus aureus.They also displayed strong activity against E. coli translocase Initially, the commercially available δ-N-Boc-R-N-Cbz-L-ornithine 17 was converted into the carboxylic acid 18 in several steps.The isonitrile 20, which was obtained in several steps from 2',3'-O-isopropylideneuridine 19, 32 reacted with the carboxylic acid 18, isovaleraldehyde 12, and 2,4dimethoxybenzylamine 21 through an Ugi reaction to afford the product 22 in 54% yield as a mixture of diastereomers (1:1).Subsequent deprotection of the diastereomeric mixture 22 in the presence of Zn and NaH2PO4, followed by treatment with TFA (80%) provided the antibacterial nucleoside natural product, (-)-MRY D2 23 along with its epimer 24.
The Ugi reaction was also used for the synthesis of sandramycin (34), a peptide natural product.In 2013, Ichikawa and co-workers synthesized the natural product 34 via Staudinger reaction, aza-Wittig reaction, diastereoselective Ugi three-component reaction (U3CR), racemization-free [5 + 5] coupling and macrolactamization (Scheme 5). 33In 1989, Matson and Bush reported the isolation of from the culture broth of Norcardioides sp.(ATCC 39419). 34This unusual peptide possesses moderate activity against Gram-positive organisms which was shown by in vitro activity assay.In particular, the in vivo evaluation of compound 34 revealed a good activity against leukemia P388 in mice.Boger and Chen in 1993 performed the first total synthesis of the natural product 34. 35The vital precursor for U3CR reaction, the isonitrile 27 was prepared in several steps from the conversation of compound 26, which was in turn obtained in 91% yield from compound 25.The synthesis of another precursor, the component-acylated serine 31, was commenced with D-Ser derivative 28 36,37 and N-Boc-N-Me-L-Val 29 38 as the starting materials.Compound 28 was reacted with compound 29 in the presence of EDCI and DMAP in CH2Cl2 to give compound 30 in 65% yield.Then, the 2,2,2trichloroethyl group was removed to provide 31 in 86% yield.The pentadepsipeptide 33 was prepared in 68% yield (S/R = 85/15) by applying a diastereoselective U3CR upon treatment of isonitrile 27 with the carboxylic acid 31 and cyclic imine 32 in toluene at 70 °C.In order to control the stereoselectivity at the new stereogenic center, the triisopropylsilyl group was introduced at the α-position to the imine 32.After several steps, the Ugi product 33 was converted into the desired antitumor antibiotic sandramycin (34) while remeving the stereogenic center that permitted the stereochemical control of the U3CR in a radical deoxygnation.In another study, Wessjohann and co-workers reported the total synthesis of antibacterial drug viridic acid (40) through the Ugi reaction (Scheme 6). 39This tetrapeptide mycotoxin was isolated from Penicillium viridicatum Westling (CSIR strain No. 354). 40The condensation reaction of the dipeptidic carboxylate 35, isobutyraldehyde 36, methylamine 37, and anthranilic isonitrile 38 under Ugi conditions yielded intermediate (±)-39 which was converted into the desired racemic viridic acid (±)-40 via saponification with LiOH at room temperature.Scheme 6. Synthesis of the tetrapeptide mycotoxin, viridic acid 40.
In a separate study, Ichikawa's group presented a convergent pathway for the total synthesis of 12membered dipeptide macrolactam 45 by a rare intramolecular three-component Ugi reaction (Scheme 7). 41yringolin A (45), has been obtained from the strains of plant pathogen Pseudomonas syringae 42 and showed inhibitory activities for the p53 mutant NB cell line LAN-1 and the p53 wild-type NB cell line SK-N-SH. 43In addition, it irreversibly and selectively inhibited the 20S proteasome through treating the S3 subsite of the b5 subunit. 44,45 he total synthesis of 45 was reported in 2009 by Huber and co-workers. 46Firstly, Boc-L-valine 41 was transformed into the isocyanoaldehyde 42 as a precursor for the intra-U3CR in several steps.Ugi reaction of 42 with 2,4-dimethoxybenzylamine 12 and the urea dipeptide carboxylic acid 43 followed by the removal of the t-butyldimethylsilyl (TBS) group to furnish the intermediate 44  The Ugi reaction was also used as a key step for the synthesis of (+)-13-demethyldysidenin ( 49) and (-)-13demethylisodysidenin (50).In 1985, Williard and Laszlo performed the total synthesis of optically pure diastereomers 49 and 50 through the Ugi reaction (Scheme 8). 47Two novel polychlorinated metabolites, demethyldysidenin (49) and demethylisodysidenin (50), were extracted from the marine sponge Dysidea herbacea. 48The one pot condensation reaction of aldehyde 46 with methylamine 37, the isonitrile 47 and acid 48 gave the desired (+)-13-demethyldysidenin (49) in 17% yield and (-)-13-demethyldysidenin (50) in 13% yield.Also, Quinaldopeptin 54 was prepared using the Ugi reaction as the key step.This natural peptide was synthesized for the first first time by solid-phase peptide synthesis in 2013 by Ichikawa and co-workers. 49In 2014, the same group reported a second-generation synthesis of this natural product through the Staudinger reaction, an aza-Wittig reaction, a diastereoselective U3CR, a [5 + 5] peptide coupling and a macrolactamization as the key steps (Scheme 9). 50In 1990, Toda et al. isolated a unique antibiotic, quinaldopeptin (54), from a culture of Streptoverticillium album strain Q132-6 51 which is highly active against Gram-positive bacteria.It also showed in vitro-activity against anaerobes and strong cytotoxic activities against B16 (marine melanoma) and Moser (human colorectal carcinoma) cells.The synthesis started with the Ugi reaction of the imine 32, the isonitrile 51 and the carboxylic acid 52 to furnish the expected pentapeptide 53 with a 84:16 diastereomeric ratio at the newly formed stereogenic center of the L-pipecolic acid residue.Then, after separation, the major diastereomer 53 was converted into quinaldopeptin (54) in several steps.Scheme 9. Application of the Ugi reaction in the total synthesis of quinaldopeptin (54).

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Schreiber and Valentekovich reported the enantiospecific total synthesis of motuporin. 52The second total synthesis of motuporin in 1999 by Armstrong and co-workers included an Ugi reaction and Matteson's dihalomethyllithium insertion methodology (Scheme 10). 53The unusual bioactive metabolite, motuporin (59), has been isolated from the marine sponge Theonella swinhoei. 54This natural product showed in vitro cytotoxicity against various cancer cell lines including murine leukemia as well as human ovarian, colon, human lung, breast, and brain cancer cell lines.Initially, the carboxylbenzyloxy (Z) protected glutamate ester 55 was reacted with aldehyde 56, cyclohexenyl isocyanide 57 and methylamine 37 under Ugi reaction conditions in the mixture of hexane and methanol to provide cyclohexenamide dipeptide 58 as a mixture of separable diastereomers in 59% yield.Then, the Ugi product 58 was transformed into motuporin (59)  Recently, the total synthesis of plusbacin A3 69 was achieved via a solvent-dependent diastereodivergent Joullié−Ugi three-component reaction (JU-3CR) (Scheme 11). 55At first, VanNieuwenhze and his research team in 2007 performed the total synthesis of 69 through a conventional peptide coupling starting from trans-Pro-(3-OH). 56Yoshida and co-workers had isolated plusbacin A3 in 1992 from the culture broth of Pseudomonas sp.PB-6250. 57This natural product displayed strongly antibacterial activities in vitro and in vivo against varied Gram-positive bacteria such as the strains of methicillin-resistant Staphylococcus aureus.The cyclic lipodepsipeptide antibiotic 69 was synthesized in several steps from the linear peptide 68 which was in turn obtained in 64% yield by condensation of amine 64 with carboxylic acid 67 in the presence of EDCl, HOAt and i-Pr2NEt.Compound 64 was prepared by reaction of isocyanide 60, imine 61 and acid 62 in 1,1,1,3,3,3hexafluoroisopropanol (HFIP) as the solvent under the JU-3CR conditions to produce the expected trans-63 (49% yield) as a major product and the cis isomer 63 )29% yield( (trans/cis = 62/38).After several steps, the major trans isomer 63 was converted into the product 64.On the other hand, Boc-D-Ser(OBn)-OH 65 was reacted with isocyanide 60 and imine 61 under the same conditions to give the desired trans-isomer 66 (51%) as along with the cis isomer-66 (37%).The product 67 was synthesized in several steps from the trans isomer trans-66.Recently, Rivera and Wessjohann presented the first total synthesis of cordyheptapeptide A 77 based on the Ugi reaction, peptide-coupling and macrocyclic-ring-closing (MRC) reaction with an overall yield of 30% (Scheme 12). 58Cordyheptapeptide A (77) is a secondary metabolite which was isolated from the insect pathogenic fungus Cordyceps sp.BCC 1788. 59This natural product exhibited strong cytotoxic activity against a wide range of cancer cell lines such as oral human epidermoid carcinoma, breast carcinoma, and human small cell lung cancer.The synthesis of target product 77 began with the reaction of L-Boc-Pro-OH 70 with paraformaldehyde (71), methylamine 37 and isonitrile 4-isocyanopermethylbutane-1,1,3-triol (IPB) 72 to prepare the intermediate 73 in 80% yield which was transformed to the compound 74 in five steps.The reaction between 74 and 75 in the presence of HATU and DIPEA in DMF at room temperature resulted in the formation of 76.Finally, the desired cordyheptapeptide A (77) was successfully obtained in three steps from 76.

Synthesis based on the Passerini reaction
The Passerini reaction is the first isocyanide-based MCR which was disclosed by Mario Passerini in 1921.It involves the condensation reaction between a aldehyde, an isocyanide, and carboxylic acid to form the αacyloxy amide. 60,61  2009, Aitken et al. presented a short and convergent pathway for the formal total synthesis of cyclotheonamide C (82) via a three-component Passerini reaction-amine deprotection-O,N-acyl migration (PADAM) strategy (Scheme 13). 62The dipeptide isonitrile 78 was condensed with the protecteddipeptide acid 79 and Fmoc-amino aldehyde 80 under Passerini reaction conditions in a mixture of CH2Cl2 and DMF to provide a 44% yield of pentadepsipeptide 81 with a ∼2:1 diastereomeric ratio (estimated by 1H NMR spectral analysis).In several steps, 81 was converted into the natural product 82.Scheme 13.The formal total synthesis of cyclotheonamide C (82) via a three-component Passerini reaction.
In 1994, the first total synthesis of a new 13-membered macrocycle, eurystatin A (87) was accomplished utilizing the Passerini reaction by Schmidt and Weinbrenner (Scheme 14). 63This natural product had been isolated from the Streptomyces eurythermus R353-21 by Toda and co-workers. 64It showed potent inhibitory activity against the serine protease prolyl endopeptidase (PEP).The total synthesis was achieved from intermediate 91 which was produced in a Passerini reaction from suitably protected ornithine 88, leucine-derived isonitrile 89 and Fmoc-L-alaninal 90 in 75% yield.Scheme 15.The total synthesis of eurystatin A (87) by Semple et al.

Miscellaneous reactions
There are several studies on the reactions for the synthesis of natural peptides which are not included in any of the previous sections.This section explores this category of reactions.
In 2008 and for the first time, Aitken and co-workers successfully accomplished the total synthesis of natural product 98 using unconventional multicomponent reaction as key step (Scheme 16). 66Fusetani et al. reported the isolation of a potent thrombin and trypsin inhibitor, cyclotheonamide C (98) from Theonella swinhoei in 1995. 67The sequence began with the preparation of intermediate 97.The precursor tripeptide aldehyde 93 was synthesized from readily available Weinreb amide 92 in several steps.The conversion of the protected dehydrotyrosine dipeptide 94 furnished amine 95 in several steps.The one pot multicomponent condensation reaction of tripeptide aldehyde 93 with amine 95 and α-(t-butyldimethylsilyloxy)malononitrile 96, using 4-pyrrolidinopyridine as a base, obtained the expected linear pentapeptide 97 in 24% yield which was converted into the cyclotheonamide C (98) over several steps.

Scheme 16. Application of multicomponent reaction in the synthesis of cyclotheonamide C (98).
In 2006, Dömling et al. presented a multicomponent reaction-based short convergent pathway for the stereoselective total synthesis of tubulysin U (104) and tubulysin V (105) (Scheme 17). 68Tubulysins are members of an interesting family of tetrapeptide secondary metabolites which were first isolated from the culture broth of the myxobacteria Archangium gephyra and Angiococcus disciformis by Höfle and co-workers in 2000.These natural products are highly active against mammalian cell lines. 69The multicomponent reaction of the commercially available Schöllkopf isocyanide 99 with thioacetic acid 100 and Boc-protected Lhomovaline aldehyde 101 in the presence of BF3•Et2O in THF provided the Boc-protected methyl ester 102 in 40% yield with a 3:1 diastereomeric ratio.Over several steps, intermediate 102 was converted into the desired natural product tubulysin U (104).In another pathway, tubulysin V (105) was prepared in a multistep sequence starting with the hydrolysis of acetate 102 to alcohol 103 in the presence of NaOH.Scheme 17.Total synthesis of tubulysin U (104) and tubulysin V (105).
In 2010, Floreancig and co-workers accomplished the total synthesis of pederin using the multicomponent reaction (Scheme 18). 70Pederin (111), a potent insect toxin, was isolated for the first time from the beetle Paederus fuscipes Curt. 71The nitrile 108 was obtained in several steps from TES-ether 107, which was synthesized by silylation of keto alcohol 106 72 using chlorotriethylsilane and imidazole.Nitrile 108 was reacted with acid chloride 109 and MeOH in the presence of the Schwartz reagent to afford the N-acyl aminal 110 in 43% yield as a single stereoisomer.Finally, removal of protecting groups in 110 gave the desired natural product 111 in 86% yield.Scheme 18. Synthesis of pederin (111), a potent insect toxin.

Conclusions
While natural peptides have been produced by various strategies, multicomponent reactions have shown a great potential among them.Multicomponent reactions reduce the number of reaction steps and increase atom economy.The present review highlights some of these approaches to demonstrate the general feasibility of the concept.

34 N 5 .
Scheme 5. Application of a multicomponent reaction in the synthesis of sandramycin(34).

in several steps. Scheme 10 .
Scheme 10.Application of Ugi reaction in the synthesis of motuporin 59.

Scheme 12 .
Scheme 12. Application of the Ugi reaction in the total synthesis of cordyheptapeptide A (77)

Scheme 14 .
Scheme 14. Application of a Passerini reaction in the total synthesis of eurystatin A (87).

Table of Contents 1 .
Introduction 2. Application of Multicomponent Reactions in the Total Synthesis of Natural Peptides 2.1.Syntheses based on the Ugi reaction in 32% over two steps.The natural product 45 was obtained from intermediate 44 in several steps.
Scheme 7. Application of Ugi reaction in the synthesis of syringolin A 45.