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Synthesis 2013; 45(10): 1271-1299
DOI: 10.1055/s-0032-1316918
review
© Georg Thieme Verlag Stuttgart · New York

Palladium-Mediated Total Synthesis of Bioactive Natural Products

K. C. Majumdar*
Department of Chemistry, University of Kalyani, Kalyani 741235, India   Email: kcm_ku@yahoo.co.in   Email: kcm@klyuniv.ac.in
,
Biswajit Sinha
Department of Chemistry, University of Kalyani, Kalyani 741235, India   Email: kcm_ku@yahoo.co.in   Email: kcm@klyuniv.ac.in
› Author Affiliations
Further Information

Publication History

Received: 22 January 2013

Accepted after revision: 14 February 2013

Publication Date:
25 April 2013 (online)

 
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This review article is dedicated to my teacher Professor S. K. Talapatra of Calcutta University on the occasion of his 80th birthday

Abstract

The search for efficient synthetic procedures for natural products, drugs, and materials with economical and ecological advantages is an important area of current interst in synthetic organic chemistry. We have made an attempt to summarize the progress made in this area since 2005. This article describes the syntheses of several natural products and drugs that employ multiple palladium-catalyzed processes in either a sequential or a domino fashion.

1 Introduction

2 Palladium-Mediated Synthesis of Alkaloids

2.1 Indole Alkaloids

2.2 Carbazole Alkaloids

2.3 Quinoline and Isoquinoline Alkaloids

2.4 Pyrrole and Pyridine Alkaloids

2.5 Pyrrolizidine and Indolizidine Alkaloids

2.6 Imidazole and Guanidine Alkaloids

2.7 Other Alkaloids

3 Palladium-Mediated Synthesis of Natural Products Containing a Sugar Moiety

4 Palladium-Mediated Synthesis of Marine Natural Products

5 Palladium-Mediated Synthesis of Amino Acids and Peptides

6 Palladium-Mediated Synthesis of Terpenoids

7 Miscellaneous Natural Products

8 Conclusion


#

Key words

palladium catalysis - natural product synthesis - biological activity - terpenoids - alkaloids - marine natural products - asymmetric allylic alkylation - C–H activation

Biographical Sketches

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Krishna C. Majumdar received his B.Sc. (1966) and M.Sc. (1968) degrees from the University of Calcutta and Ph.D. from the University of Idaho (USA), completed his doctoral thesis in 1972 under the direction of Professor B. S. Thyagarajan and continued in the same university as a research associate until mid-1974. He then carried out postdoctoral work at the University of Alberta with Professor J. W. Lown until mid-1977. After returning to India, he held appointments with the University of Kalyani, as lecturer (1977), reader (1984), and professor (1995), and is presently a UGC Emeritus Fellow at the same university. He had also served North-Eastern Hill University as a visiting professor (1996), Indian Institute of Technology (Kharagpur) as associate professor (1990–1991), and Tezpur University (2011) as Professor of Eminence. His research interests centered around synthetic organic chemistry with over 380 publications. His recent research interests also include the design and synthesis of liquid crystals. He is a Fellow of the West Bengal Academy of Science and Technology, and recipient of the Chemical Research Society of India Medal (2004) and Indian Chemical Society Award (2006).

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Biswajit Sinha was born in Krishnagar (Nadia), West Bengal. He received his B.Sc. in 2004 and M.Sc. in 2006 from the University of Kalyani. He then joined the research group of Prof. K. C. Majumdar at the University of Kalyani with a CSIR (NET) fellowship. He is mainly working on metal-mediated synthesis of heterocycles and molecular iodine mediated synthesis of potentially bioactive heterocycles.

1 Introduction

Throughout the history of isolation and characterization of natural products, their total synthesis has been a major area of research interest.[1] This is because around half of the drugs currently used in clinical applications have their origin in natural products.[2] Moreover, the complex structure – and, in most cases, the challenging stereochemistry – demand robust, selective methods and suitable reagents for their synthesis. Palladium-mediated protocols have been found to be quite efficient for the formation of carbon–carbon and carbon–heteroatom bonds.[3] The efficiency of palladium-catalyzed reactions has been validated especially in the synthesis of structurally complex natural products synthesis due to its functional group tolerance and high regio- and stereospecificity. Palladium-mediated reactions are widely applied in target synthesis either in the cyclization steps in appropriate situations or by assembling different important fragments as required. The Heck, Stille, Suzuki, Sonogashira, Tsuji–Trost and Negishi reactions are the frequently applied palladium-catalyzed carbon–carbon bond-forming reactions in total synthesis that often offer particular emphasis in maintaining the proper stereochemistry.[4] There are different literature reviews available that deal with the total synthesis of natural products[5] by different methods, but only rarely covering the use of palladium as the choice reagent.[6] In this review, we have attempled to summarize a number of recently accomplished total syntheses of natural products possessing interesting biological ativities where palladium-based reagents are used as the key steps in the construction of their basic frameworks.[7] We mainly focus on the total synthesis of biologically and pharmacologically important natural products reported since 2005.


# 2

Palladium-Mediated Synthesis of Alkaloids

Palladium catalysis has been used to synthesize a vast number of alkaloids, most of which have either important properties within a broad spectrum of biological activities, or interesting molecular architecture, or both. The main structural motifs include indole, pyrrole, quinoline, imidazole and isoquinoline frameworks.[8]

2.1

Indole Alkaloids

The pharmacologically important ergot alkaloids contain a [cd]-fused indole ring along with the Δ9,10-double bond and chiral centers at C5 and C8. Many of these are produced by filamentous fungi such as Claviceps purpurea and exhibit broad biological activity.[9] Recently, clavicipitic acid, a derailment product of ergot alkaloid biosynthesis, has been synthesized utilizing a palladium-catalyzed indole synthesis as well as a palladium-catalyzed Heck reaction.[10]

(+)-Lysergol (4), (+)-isolysergol (5) and (+)-lysergic acid (6) are also important classes of ergot alkaloid which possess characteristic structural features and biological activities. These were recently synthesized using a palladium-catalyzed domino cyclization of a chiral allene to construct the C/D ring system as well as simultaneously forming the C5 chiral center. The reaction of 2 in the presence of Pd(PPh3)4, potassium carbonate in N,N-dimethylform­amide at 100 °C provided the tetracycle 3 in 76% yield with good diastereoselectivity.[11] The reaction does not suffer from the presence of the free hydroxyl group. The tetracycle 3 was also later synthesized from the alkynyl substrate 1. In this case, the alkynylic compound 1 initially undergoes reaction to produce the allenic compound 2 which under the aforesaid cyclization conditions afforded the desired product 3, the important intermediate to access compounds 4–6 (Scheme [1]).[12]

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Scheme 1

A number of sarpagine and ajmaline alkaloids, including (+)-12-methoxy-N a-methylvellosimine (12a), (+)-12-meth­oxyaffinisine (12b), (+)-12-methoxy-N b-methylvellosimine (12c) and (–)-11-methoxy-17-epivincamajine (13) were isolated from the bark of Rauwolfia bahiensis and Peschiera fuchsiaefolia [13] and their first enantiospecific total syntheses were reported by Cook et al.[14] Some of these natural products possess inhibition activities, for instance against avian myeloblastosis virus reverse transcriptase, or complete inhibition of South American rattle snake venom in rats upon injection 20 seconds after it had been injected with twofold the LD50 (1.7 mg/100 g) of the venom.[15] All four of these natural products were synthesized through the same intermediate 11 that itself was easily synthesized by a process involving two palladium-catalyzed reactions.

The indole moieties 9 were prepared in 75 and 77% isolated yields via Larock heteroannulation[16] of 7 with the propargyl-substituted Schollkopf chiral auxiliary 8 in the presence of palladium(II) acetate, potassium carbonate and lithium chloride as the catalytic system in N,N-dimethylformamide at 100 °C. A few more steps afforded the intermediate ketones 10. When ketones 10 were subjected to enolate-driven palladium-catalyzed intramolecular cyclizations, the pentacyclic ketones 11 were obtained in 80 and 82% yields, with the C19–C20 (E)-ethylidene function established in a stereospecific fashion (Scheme [2]).

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Scheme 2

Earlier, a concise approach to the core skeleton of the welwitindolinone alkaloids had been developed on the basis of a palladium-catalyzed enantioselective [6+3] trimethylenemethane cycloaddition reaction.[17] Recently, a total synthesis of N-methylwelwitindolinone D isonitrile, 17, the first member of the bicyclo[4.3.1]decane family, was reported.[18] This total synthesis involved a Lewis acid mediated alkylative coupling followed by a palladium-catalyzed intramolecular arylation to assemble the tetracyclic carbon scaffold in only seven steps from commercially available material 14. The alkaloid N-methylwelwitindolinone D displays a wide variety of biological activities, ranging from antifungal activity to microtubule depolymerization.[19] During its total synthesis the bicyclo[4.3.1]decane framework was expected to be accomplished using a palladium-catalyzed intramolecular enolate arylation to form the key C4–C11 bond which is, perhaps, the most difficult and interesting step from the stereochemical view point. Apparently this is quite challenging because it would set in place the vicinal quaternary stereocenters. The intramolecular coupling reaction of 15 under optimized conditions using palladium(II) acetate and tri-tert-butylphosphine (1:1) in the presence of potassium hexamethyldisilazide (KHMDS) in toluene gave satisfactory results and the cyclic product 16 was obtained in 73% yield (Scheme [3]). Compound 16 possesses the bicyclo[4.3.1]decane core, common to the majority of the welwitindolinones.

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Scheme 3

Curan-type strychnos alkaloids form an important group of widely distributed complex monoterpenoid indole alkaloids.[20] The molecular framework of the curan family consists of the pentacyclic 3,5-ethanopyrrolo[2,3-d]carbazole scaffold 20.[21] (±)-Strychnine (23), and its pentacyclic analogues 21 and 22, are important members of this family. Owing to their complex molecular framework and bioactivities, a number of attempts have been made to synthesize the heptacyclic alkaloid strychnine[22] [23] though the related pentacyclic curan family of comounds has received far less attention. The Padwa research group employed a palladium-catalyzed cyclization strategy to construct the D/E ring and successfully synthesized several pentacyclic curans: (±)-tubifolidine (21), (±)-strychnopivotine (22a), (±)-valparicine (22b) and (±)-strychnine (23). The key step of the total syntheses is a palladium-catalyzed intramolecular coupling of 18 to construct the crucial D ring using tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] and potassium phenolate as the catalytic system. The reaction proceeded smoothly to furnish aza-pentacycles 19 in good yield. The common intermediates 19 underwent reaction under different conditions to afford the natural products 21, 22 and 23 (Scheme [4]).[24a] [b]

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Scheme 4

A number of research groups[24c] [d] have also taken up the challenge to synthesize (±)-strychnine. Besides a samarium(II) iodide induced cascade reaction or a [4+2]-cycloaddition reaction as the key step, palladium(II) acetate or Pd(PPh3)4-catalyzed reactions have also been used in the cyclization step, thus proving the usefulness of the palladium reagent in total synthesis of (±)-strychnine.

The secoiridoid indole alkaloid minfiensine (28) was isolated from Strychnos minfiensis and possesses an abnormal molecular formula when compared to other strychnos alkaloids.[25] The Overman research group undertook the first total synthesis of minfiensine (28) by combining a palladium-catalyzed asymmetric Heck cyclization with an intramolecular iminium ion cyclization.[26] Initially, a reductive Heck cyclization strategy was used to form the fifth ring to complete the total synthesis of (+)-minfiensine, but the reaction suffered from side reactions resulting from facile ring opening of the pyrrolidinoindoline subunit. To overcome the difficulty, an alternative synthesis was designed, employing a palladium-catalyzed intramolecular enolate–vinyl iodide coupling strategy. In the presence of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [Pd(dppf)Cl2] and potassium carbonate as the catalytic system in methanol at 70 °C, intermediate 25 afforded the pentacyclic fragment 27 in 74% yield (Scheme [5]). This alternate protocol afforded enantiopure (+)-minfiensine 28 in 6.5% overall yield. In the presence of N,N-dimethylformamide or acetonitrile as solvent, the cyclized product formation was suppressed and deallylation was observed.

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Scheme 5

Willis and co-workers[27] recently used a palladium-catalyzed oxindole arylation reaction for the total synthesis of hodgkinsine B, which is present in a variety of flora and fauna[28] and exhibits biological activities including antibacterial, antifungal, antiviral, cytotoxic and analgesic properties.[29]


# 2.2

Carbazole Alkaloids

Carbazole alkaloids have attracted much attention and intense research activity because of their profound pharmacological potential.[30] Recently, a number of carbazole alkaloids, including clausenol, clausine I, clausine Z,[31a] murrayafoline A,[31b] [c] [d] and 2-methoxy-3-methylcarbazole,[31e,f] were synthesized using palladium-catalyzed double C–H bond activation processes as key steps. All of these natural products are biologically very important for their inhibition activities against some bacteria, blood platelet aggregation and cyclin-dependent kinase 5 (CDK5). The first total synthesis of the potent antioxidant antiostatin A was reported by Witulski and co-workers,[31g] who used a palladium-catalyzed arylamidation reaction. Almost simulteneously, Knölker and co-workers described the first total syntheses of the whole series of the antiostatins A1–A4 and also of the antiostatins B2–B5, which are structurally much more complex as they contained an unprecedented biuret side chain.[31h]

Wu et al. isolated[32] euchrestifoline from the leaves of Murraya euchrestifolia and its first total synthesis was reported by the Knölker group,[33] who employed three consecutive palladium-catalyzed reactions, namely a Buchwald–Hartwig amination, a Wacker oxidation, and a subsequent oxidative biaryl cyclization by double aromatic C–H bond activation. A one-pot palladium-catalyzed approach was found to be more effective, as it provided euchrestifoline in 37% overall yield.


# 2.3

Quinoline and Isoquinoline Alkaloids

The melodinus alkaloids are a family of dihydroquinolinone natural products that are structurally related to the aspidosperma alkaloids. Melodinus alkaloids such as (+)-scandine and (+)-meloscandonine feature a congested cyclopentane core bearing four contiguous stereocenters.[34] In order to synthesize the melodinus alkaloids, the Stoltz research group developed a strategy to construct the core of the natural product family, including the C16 quaternary stereocenter.[35a] The tetracycle 32 was utilized as a model for evaluating this strategy using palladium-catalyzed [3+2] cycloaddition of a vinylcyclopropane. Known vinylcyclopropane 20 was prepared according to a literature procedure and reaction of this cyclopropane with commercially available β,2-dinitrostyrene (29) under conditions similar to those developed by Tsuji[35b] resulted in the formation of vinylcyclopentane 31 in 60% yield as a mixture of two inseparable diastereomers (Scheme [6]). Compound 31, after a few steps, afforded tetracycle 32, the tetracyclic core structure of (+)-scandine (33).[35a]

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Scheme 6

The total synthesis of the alkaloids cis- and trans-195A, possessing intriguing pharmacological properties and a unique structure,[36] was achieved utilizing a palladium-catalyzed oxidative cyclization reaction as a key step.[37]

An important member of the isopavine family of alkaloids, amurensinine (35), possesses a characteristic tetracyclic tetrahydroisoquinoline core consisting of a doubly benzannulated azabicyclo[3.2.2]nonane[38] ring. This isopavine is used in the treatment of neurological disorders, such as Parkinson’s and Alzheimer’s diseases.[39] Stoltz and co-workers utilized[40] a palladium-catalyzed oxidative kinetic resolution in the synthesis of enantioenriched amurensinine [(+)-35]. The hydroxysilane (±)-34, prepared by reduction of the hydroxy ester, was subjected to oxidative kinetic resolution conditions to provide the alcohol (–)-34 in 47% yield and >99% enantiomeric excess (Scheme [7]). The reaction is unique in character as it offered the first demonstration of oxidative kinetic resolution in the context of natural product synthesis.

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Scheme 7

# 2.4

Pyrrole and Pyridine Alkaloids

The Trost reseach group gave a full account[41] of their recent development of palladium-catalyzed pyrrole- and N-alkoxyamide-based asymmetric allylic alkylation (AAA) reactions. Applying the same methodology, they also achieved enantioselective total syntheses of both (–)- and (+)-agelastatin A (41a and 41b) via two different routes involving a chiral palladium catalyst. Agelastatin A (41) was first isolated in 1993 by Pietra and co-workers from the deep-water marine sponge Agelas dendromorpha.[42] It exhibits exceptional biological activities; notably, nanomolar activity against a broad range of cancer cell lines that includes human KB nasopharyngeal cancer cells.[43] The unusual 5,6,5,5-fused tetracylic system, including a bromopyrrole motif and four contiguous stereocenters on a five-membered ring, make it an interesting target for synthesis. The palladium-catalyzed AAA reaction of 36 and 37 gave pyrrolopiperazinone 38, the key intermediate for the formation of (+)-41b after few steps and modifications. The alternative route, namely a palladium-catalyzed one-pot cascade AAA reaction of 36 and 37, afforded the tricyclic pyrrolopiperazinone framework 40a more efficiently in a single step. Formation of 40a is crucial from the synthetic viewpoint as it can effectively be transformed to (–)-41a in few steps (Scheme [8]).

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Scheme 8

Butylcycloheptylprodigiosin (47) was isolated from Streptomyces sp. Y-42 and Streptomyces abikoensis (formerly Streptoverticillium rubrireticuli) and Gerber later assigned this as a novel member of the prodigiosin family.[44] A formal total synthesis of 47 was carried out by the Fürstner research group, who applied a Narasaka–Heck cyclization[45] [Pd(OAc)2 and (o-tolyl)3P in DMF at 110 °C] to form the unsaturated bicyclic imine 45, the key intermediate, in 54% yield. Notably, as compound 45 was highly unstable, it was immediately used for further reaction. A few steps afforded 46, which, upon exposure to boronic acid 48 in the presence of a catalytic amount of Pd(PPh3)4 and lithium chloride under optimized conditions, afforded the prodigiosin 47 in 61% yield (Scheme [9]).[46]

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Scheme 9

Anibamine (53), a quaternary pyridine alkaloid isolated from Aniba panurensis,[47] has been identified as a chemokine receptor CCR5 antagonist with an IC50 of 1 μM in inhibiting the binding of 125I-gp120 to the CCR5 receptor. Anibamine possesses a novel structural skeleton containing a fused quaternary nitrogen ring in its core structure along with a couple of long chains. The first total synthesis of anibamine was recently reported by Zhang and co-workers.[48] The two ten-carbon side chains were introduced by the reaction of the Wittig reagent created from 1-bromononane with the 3,5-dialdehyde pyridine intermediate. Unfortunately, four isomers were obtained as an inseparable mixture and at the last step, 53 was isolated by preparative HPLC in only 8% overall yield (10 steps). This synthetic route suffered from tedious separations in the last few steps and relatively low yield due to limited stereoselectivity of the Wittig reaction. Thus, the reaction protocol was revised. The syntheses of 53 and its three olefin isomers was achieved concisely and efficiently via highly regio- and stereoselective reactions which included a regioselective palladium-catalyzed alkynylation by Sonogashira coupling and a stereoselective Suzuki coupling (Scheme [10]). Under standard Suzuki reaction conditions,[49] one equivalent of 51 and four equivalents of diisopropyl (Z)-1-decenylboronate were coupled in the presence of palladium(II) acetate, triphenylphosphine and sodium carbonate in a mixed solvent system (toluene–EtOH–H2O, 2:1:1) at reflux temperature for six hours. The two aliphatic side chains were stereoselectively introduced at positions 3 and 5 of the intermediate 51 to give 52 stereoselectively in excellent yield.[50]

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Scheme 10

# 2.5

Pyrrolizidine and Indolizidine Alkaloids

Australine, a potent and specific glycosidase inhibitor, was isolated from the rainforest tree Castanospermum australe [51] and is an inhibitor of α-glucosidase amyloglucosidase.[52] Its highly oxygenated bicyclic core structure containing five contiguous stereogenic centers as well as its resemblance to several structurally related alkaloids (differing mainly in the stereochemical orientation[53]) made australine a particularly interesting target for synthesis. Trost and co-workers applied the palladium-catalyzed asymmetric allylic alkylation (AAA) in the synthesis of australine starting from oxazolidinone 54, itself easily prepared in three steps from 1,2-divinylethylene carbonate in high yield. Under the optimized conditions, 54 was subjected to reaction with butadiene monoepoxide in the presence of 0.5 mol% Pd2(dba)3·CHCl3, 1.5 mol% ligand and 10 mol% 1,8-diaza­bicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane to afford a mixture of ring-opened products 55a and 55b. Using the (R,R)-naphthyl ligand, the diastereomer 55a was preferentially formed along with 55b as an inseparable mixture in a 95:5 ratio; after a few steps, australine (56) was obtained (Scheme [11]).[54]

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Scheme 11

A palladium-catalyzd cyclization strategy was successfully applied to the synthesis of the pyrrolizidine alkaloid (–)-trachelanthamidine (59).[55] The amide 57 was obtained by Johnson–Claisen rearrangement[56] of a protected butenediol, hydrolysis, and treatment with p-tosylisocyanate. When treated with 5 mol% of palladium(II) chloride, lithium chloride and TIPS-EBX (60) in ethanol at room temperature, 57 gave rise to the cyclic product 58 in 72% yield. The racemic trachelanthamidine 59 was obtained in 22% overall yield (Scheme [12]).[57]

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Scheme 12

3-Azabicyclo[3.3.0]octanes and 3-azabicyclo[4.3.0]nonanes are prevalent structural subunits in bioactive natural products such as dendrobine and α-skytanthine.[58] Toyota and Takeda carried out a second-generation palladium-catalyzed cycloalkenylation of the lactam ester 61 in the presence of palladium(II) acetate (10 mol%) and dimethyl sulfoxide (5 equiv) at 45 °C in toluene under an atmosphere of oxygen to afford the cyclized product 62 in 70% yield as a mixture of olefin isomers (Scheme [13]). The complex mixture, without separation, was subjected to further reactions to give α-skytanthine (63).[59]

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Scheme 13

The O’Doherty research group achieved[60] enantioselective syntheses of both enantiomers of the indolizidine natural product swainsonine (65), a potent glycosidase inhibitor,[61] in 13 steps from furan. A diastereoselective palladium-catalyzed glycosylation of 64, prepared from 2-lithiofuran, in the presence of palladium(II) hydroxide afforded (+)-swainsonine (65) in 88% yield (Scheme [14]).

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Scheme 14

# 2.6

Imidazole and Guanidine Alkaloids

The guanidine alkaloids merobatzelladines A and B were isolated from the marine sponge Monanchora sp. [62] and possess moderate antimicrobial activity against Vibrio anguillarum and show inhibitory activity against the K1 strain of Plasmodium falciparum. Because of the significant biological activities exhibited by guanidine alkaloids, several research groups have reported highly useful total synthesis routes using mostly condensation,[63] cycloaddition[64] and radical cyclization[65] steps to generate the fused-ring system of merobatzelladines A and B. To overcome the problems associated with these synthetic routes and to access the natural product as a single stereoisomer in high optical purity, the Wolfe research group developed the first total synthesis of merobatzelladine B (71) using, as key steps, palladium-catalyzed alkene carboamination reactions for the construction of the ring systems, with excellent stereocontrol (Scheme [15]). The asymmetric total synthesis is highly useful as it confirms the structural and stereochemical assignments of the natural product (+)-merobatzelladine B (71) as well as afforded the desired alkaloid in 15 steps and in 6.7% overall yield from the commercially available pent-4-enal (66).[66]

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Scheme 15

The palladium-catalyzed decarboxylation and carbonylation of a 1,3-dioxan-2-one to form a γ-butyrolactone ring, an important intermediate, was used for the total synthesis of the naturally occurring imidazole alkaloid pilocarpine.[67] Pilocarpine is a peripheral stimulant of the parasympathetic system and has been used as both an amiotic and a diaphoretic agent.[68]


# 2.7

Other Alkaloids

A palladium-catalyzed tandem cyclization and cross-coupling reaction of triethyl(indol-2-yl)borate with vinyl bromide was successfully used in the concise total synthesis of the indolophenanthridine alkaloids, calothrixins A and B.[69] Calothrixin A (78) and calothrixin B (79), isolated from the lyophilized extracts of Calothrix cyanobacteria, possess an unusual pentacyclic indolo[3,2-j]phenanthridine system[70] and inhibit the growth of human HeLa cancer cells. They also act as human topoisomerase I poisons and reversibly stabilize the topoisomerase–DNA binary complex leading to cell death.[71] It was also observed[72] that indolylborate 73, a tetracoordinate complex, showed high reactivity in palladium-catalyzed cross-couplings for the synthesis of indole derivatives. To expand the scope of this reaction, compound 73 (generated in situ from 1-meth­oxyindole and n-butyllithium in tetrahydrofuran, followed by treatment with triethylborane) was treated with 74 in the presence of the palladium complex Pd2(dba)3·CHCl3 in tetrahydrofuran at 60 °C under an argon atmosphere to generate triene 77, the key intermediate for the formation of calothrixins A and B (Scheme [16]). The catalysis was supposed to initiate the oxidative addition of the catalytically active palladium(0) species with the bromide 74 to produce the vinylpalladium complex 75a. The intramolecular cyclization of 74 followed by coupling with 73 resulted in the formation of complex 76. Triphenylphosphine might stabilize the tetracoordinate complex 75b, thus providing the opportunity for side reactions to occur. In contrast, coordination of bulky tri(o-tolyl)phosphine shifted the equilibrium between 75a and 75b towards the less crowded tricoordinate complex 76. Reductive elimination of Pd(0)L from 76 furnished the triene 77.

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Scheme 16

Aromatic benzo[c]phenanthridine alkaloids, such as sanguinarine 80, show interesting biological activities; for example, 80 inhibits lipoxygenase and mediates chemical defense against microorganisms, virus and herbivores in plants.[73] The other alkaloids, chelerythrine, avicine and nitidine, inhibit protein kinase C and DNA topoisomerase I.[74] The palladium-catalyzed tandem coupling–cyclization of functionalized o-iodobenzoates 81 with azabicycle 84 under the optimized conditions [Pd(PPh3)2Cl2, Zn, ZnCl2, Et3N, THF] was found to be effective for the total syntheses of natural benzo[c]phenanthridine alkaloids. The reaction is presumed to occur as follows: (i) reduction of palladium(II) by zinc to palladium(0); (ii) oxidative addition of ArI to the palladium(0) species to form Pd(PPh3)2ArI complex 83; (iii) exo addition of Ar–Pd to the azabicyclic alkene 84 to afford the intermediate 85, and successive β-heteroatom elimination to produce the ring-opened intermediate 86; and, finally, (iv) transmetalation of 86 with zinc chloride, followed by an amidation and deprotection of the Boc group to produce the tandem ring-opening and coupling benzo[c]phenanthridinone products 82 and regeneration of the palladium(II) species (Scheme [17]).[75]

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Scheme 17

The phenanthroindolizidine alkaloid (–)-tylophorine was first isolated in 1935 from the perennial climbing plant Tylophora indica.[76] It attracted much attention due to its cytotoxic activity by a novel mechanism of action.[77] Recently, a total synthesis of the racemic natural product tylophorine (±)-92 was reported; it used the palladium-catalyzed Wolfe carboamination method. In this case, the electron-rich aryl bromide 90 was prepared from 87 and 88 using a palladium-catalyzed Sonogashira coupling as one of the key steps. It was then subjected to a palladium-catalyzed Wolfe carboamination with an olefinic carbamate to afford the racemic 2-(arylmethyl)pyrrolidine (±)-91, a key intermediate toward racemic tylophorine, in good yield (Scheme [18]).[78]

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Scheme 18

A palladium-catalyzed enantioselective reaction was successfully applied[79] in the total synthesis of securinine and (–)-norsecurinine, the securinega alkaloids include a group of compounds isolated from some plants of the Securinega­ and Phyllanthus species.[80]

Lavendamycin, a bacterially derived antitumor antibiotic, was isolated from Streptomyces lavendulae. This exhibits activity against several cancer cell lines and topoisomerase I.[81a] [b] Lavendamycin has a highly functionalized pentacyclic structure consisting of β-carboline and quinoline-5,8-dione moieties.[81c] Recently, Nissen and Detert­ reported a concise total synthesis of lavendamycin using a palladium-catalyzed cross coupling as a key step.[82]

Manzamine A, ircinol A, and ircinal A are three structurally complex marine natural products that show interesting bioactivities including insecticidal, anti-bacterial, anti-inflammatory, anti-cancer, and anti-malarial activities.[83] Dixon and co-workers very recently reported their total synthesis starting from a common intermediate, 93. Notably, palladium catalysis was not used in the complex cyclization steps but was judiciously employed for introducing different necessary functional groups in compound 93 to access manzamine A (95), ircinol A (96a) and ircinal A (96b) in good yields (Scheme [19]).[84]

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Scheme 19

#
# 3

Palladium-Mediated Synthesis of Natural Products Containing a Sugar Moiety

Anthrax is a zoonotic disease caused by the spore-forming bacterium Bacillus anthracis.[85] Its protective polypeptide capsule consists of poly-d-glutamic acid, which inhibits phagocytosis.[86] Recently, anthrax tetrasaccharide 104, made up of three l-rhamnose sugars and the rare sugar d-anthrose, was isolated from the capsule. The uniqueness of the anthrose sugar and the resistance of carbohydrate structures to evolutionary change make the anthrax tetrasaccharide an interesting target for anthrax detection and vaccine development.[87] O’Doherty and Guo[88] developed a de novo asymmetric synthesis of the natural product anthrax tetrasaccharide in 25 steps (longest linear; 39 total steps) from achiral acetylfuran 98, with palladium-catalyzed heterocyclizations as key coupling steps. Repeatedly using the palladium-catalyzed glycosylation reaction [BnOH, 0.25% Pd(0)/0.5% Ph3P] – developed in their own laboratories – on the axial C2-hydroxyl group in 100 with pyranone ent-99 and on the C3 hydroxyl of 102 with ent-99, they successfully prepared 103. After several additional steps, the anthrax tetrasaccharide 104 was obtained in 13% overall yield (Scheme [20]).

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Scheme 20

O’Doherty and Guo also developed[89] an asymmetric approach to the natural product anthrax tetrasaccharide and an analogue possessing an anomeric hexyl azide group, starting from acetylfuran. The construction of the tetrasaccharide was achieved by an iterative diastereoselective palladium-catalyzed glycosylation, Luche reduction, diastereoselective dihydroxylation, and regioselective acylation as key steps for the assembly of the l-rhamno-trisaccharide building block. The anthrax tetrasaccharide was thus achieved in a comparatively shorter route (25 steps and in 13% overall yield) from the same achiral starting material acetylfuran (98).

A similar diastereoselective palladium-catalyzed glycosylation reaction was used for the synthesis of several cleistrioside and cleistetroside natural products which possess significant antimicrobial activity against several strains of methicillin-resistant Staphylococcus aureus.[90]

Digitoxin (108) is a glycoside, isolated from the leaves of Digitalis purpurea (purple foxglove), used to slow the heart rate while increasing the contractility of the heart muscles (inotropic activity). It has also been used for the treatment of congestive heart failure and cardiac arrhythmia for over 200 years.[91] Structurally, digitoxin is the combination of two natural products, the aglycon digitoxigenin (106)[92] and the trisaccharide digoxose (105).[93] Although a number of synthetic methods are available in the literature for the construction of digitoxigenin (106), there was no synthesis of the natural product digoxose (105) until 2006. In 2007, O’Doherty and Zhou reported[94] a highly enantioselective and straightforward route to the trisaccharide natural products digoxose (105) and digitoxin (108) that involved a palladium-catalyzed glycosylation reaction, a reductive 1,3-transposition, a diastereoselective dihydroxylation, and regioselective protection.

The key step in this total synthesis was the palladium-catalyzed glycosylation of the pyranone 99b. The palladium(0) and triphenylphosphine catalyzed glycosylation strategy starting from digitoxigenin (106) and β-pyranone 99b afforded the digitoxigenin mono-digitoxoside 107 in good yield (Scheme [21]). During the reaction both the tertiary alcohol and the butenolide ring of the aglycon were left untouched. This route provides the first total synthesis of digitoxin (108) in 15 steps from digitoxigenin (106) and β-pyranone 99b. Thus the first total synthesis of digitoxin (108) was accomplished in 15 steps from digitoxigenin (106) and β-pyranone 99b.

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Scheme 21

The papulacandins constitute a family of glycolipids that exhibit potent in vitro antifugual activity against Candida albicans, C. tropicalis, Pneumocystis carinii, and related microorganisms.[95] Earlier the O’Doherty research group had reported two de novo approaches to the papulacandins from achiral starting materials to prepare the carbohydrate portion of the natural product.[96a] [b] [c] Recently, a concise total synthesis of papulacandin D was reported by Denmark et al.,[96d,e] wherein a palladium-catalyzed cross-coupling reaction was used as one of the key steps. The vital cross-coupling reaction of 110 and the appropriate aromatic iodide was carried out with 5 mol% Pd2(dba)3·CHCl3 as the catalyst and two equivalents of sodium tert-butoxide as the activator at 50 °C for five hours (Scheme [22]).

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Scheme 22

Cytopiloyne (113), a β-O-glucopyranoside, possesses a glucose moiety and a tetrayne aglycone unit. This effectively controls and prevents type 1 diabetes in non-obese diabetic mice and also effective in controlling type 2 diabetes in dβ/dβ mice.[97] Lee and co-workers described[98] the first total synthesis of two diastereomers of cytopiloyne (113a and 113b) and assigned the absolute stereochemistry (at C2) of the natural product on the basis of the following disconnection approach (Scheme [23]).

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Scheme 23

Compounds 116 and 117 were prepared following standard procedure. They were then subjected to copper(I) iodide mediated Sonogashira coupling in the presence of Pd(PPh3)2Cl2. Unfortunately, the tetra-alkyne 121 was obtained in poor yield of less than 5% (Scheme [24]). The tetra-alkyne 121 decomposed readily when left to stand at room temperature, perhaps owing to the inherently unstable nature of the longer polyynes.[99] This observation prompted the researchers to devise an alternative strategy.

Iodoalkyne 117 and β-glucosyl alkyne 122 were prepared individually and their Sonogashira coupling was performed with Pd(PPh3)2Cl2 and copper(I) iodide as catalyst in tetrahydrofuran to furnish the fully protected cytopiloyne 113 in only trace quantity. Alternatively, the palladium-and-silver-catalyzed coupling[100] of iodoalkyne 118 (prepared by the iodination reaction of 122) with silyl-protected triyne 119 in the presence of potassium carbonate, methanol, silver fluoride and Pd(PPh3)4 gave the desired tetrayne in 36% yield (Scheme [25]). Deprotection of the p-methoxybenzyl and acetyl groups afforded cytopiloyne 113a as a colorless solid but its spectroscopic and optical rotation data did not match that of the natural product.

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Scheme 24
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Scheme 25

Another alternative approach, starting from (4R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (120) in a similar reaction sequence including palladium-catalyzed coupling reaction, was found to be successful (Scheme [26]). (2R)-Cytopiloyne (113b) was accomplished in 1.6% overall yield over 10 steps. The characterization data of 113b were found to be identical in all respects to those of the natural product cytopiloyne isolated from the natural source.

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Scheme 26

She and co-workers constructed a tetrasubstituted cis-tetrahydropyran ring with high stereoselectivity by employing­ a palladium-catalyzed intramolecular alkoxycarbonylation as the key step.[101] The total synthesis of cyanolide A was thus accomplished in 14 steps from commercially available (S)-2-ethyloxirane. Cyanolide A is a highly potent molluscicidal agent against the snail vector Biomphalaria glabrata.[102]


# 4

Palladium-Mediated Synthesis of Marine Natural Products

Natural products from marine sources, many with important types of biological properties, have yielded some of the most complex synthetic challenges in recent years. Pachastrissamine (126), an anhydrophytosphingosine derivative, was isolated by Higa and co-workers from the Okinawan marine sponge Pachastrissa sp. in 2002.[103a] After its isolation from the Vanuatuan marine sponge Jaspis sp., Debitus and co-workers named the same compound as jaspine B.[103b] Jaspine B displays remarkable cytotoxic activity against several tumor cell lines. In 2009, Ohno and co-workers reported[104a] that bromoallenes bearing hydroxyl and benzamide groups as internal nucleophiles, upon palladium(0)-catalyzed stereoselective cyclization, afforded the functionalized tetrahydrofuran 125a. Pachastrissamine/jaspine B (126), bearing three contiguous stereogenic centers, was thus synthesized from Garner’s aldehyde[105] (123) in 11 steps and 11% overall yield (Scheme [27]).

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Scheme 27

Another novel ring construction and stereoselective functionalization cascade by palladium(0)-catalyzed biscyclization of propargylic carbonates or chlorides to synthesize jaspine B was developed[104b] by the same research group. The reaction of propargyl carbonate 127 (again, prepared from Garner’s aldehyde) in the presence of Pd(PPh3)4 in tetrahydrofuran at 50 °C afforded the desired bicyclic tetrahydrofuran 125b in 69% yield. This then furnished pachastrissamine/jaspine B in 26% overall yield in seven steps (final deprotection by hydrolysis) or 28% overall yield in eight steps (reductive deprotection) from 123 (Scheme [28]). This methodology was also utilized to offer divergent syntheses of various pachastrissamine derivatives containing different alkyl groups at the C2 position. This route is much better than their previously reported procedure, not only in terms of increasing the overall yield, but also by decreasing the total number of steps.

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Scheme 28

The secondary metabolites known as aspergillides A, B and C were isolated from a marine-derived fungus, Aspergillus ostianus strain 01F313, and display cytotoxic activity against mouse lymphocytic leukemia cells (L1210) with LD50 values of 2.1, 71.0, and 2.0 μg/mL.[106] Walters and Panarese achieved the total synthesis of aspergillide C (131) in a simple and straightforward manner by applying a palladium-catalyzed Wacker-type oxidative lactonization of (+)-129 to produce (+)-130 (Scheme [29]).[107]

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Scheme 29

(+)-7,11-Helianane and (+)-5-bromo- and (+)-5-chloro-7,11-helianane, the secondary metabolites of sunflowers (Helianthus annus), were isolated from the marine sponges Haliclona fascigera and Spirastrella hartmani, respectively.[108] By employing a well-known palladium-catalyzed asymmetric allylic alkylation reaction, Papeo and co-workers recently succeeded in synthesizing these natural products.[109]

The iejimalides are a class of marine natural macrolides, isolated from the tunicate species eudistoma cf. rigida,[110] that possess a unique structural architecture consisting of a 24-membered polyene macrolide core along with five chiral centers and four dienes. Though all members of the iejimalide family show potent growth inhibitory activity against a wide range of human tumor cell lines, iejimalide B was found to be most effective. It is also cytostatic (GI50) at <5 nM against 40 of the 60 cell lines tested in the NCI cancer screen. Recent studies at the NCI have shown that the iejimalides may have an under-explored mode of anticancer activity. It also belongs to the privileged class of natural products that show inhibition of V-ATPase.[111]

Owing to their increasing biological importance and complex molecular architecture, several attempts have been made to synthesize the iejimalides. The Helquist research group reported a synthesis of iejimalides, though the reaction suffered severely during macrolactonization in the penultimate step.[112] Later, the reaction strategy was improved by accomplishing the construction of the macrocycle by a Keck-type intermolecular esterification of the two major subassemblies, followed by an intramolecular Stille coupling reaction of 137 under conditions involving a Pd2(dba)3·CHCl3, triphenylarsine and diisopropylethylamine catalytic system.[113] An earlier attempt to prepare compound 137 using an intramolecular Sonogashira-type reaction with a catalytic system comprised of Pd(dppf)Cl­2, tributyltin hydride and tetrahydrofuran was unsuccessful, so a modified reaction strategy was developed. Compound 135 was prepared from 134, and the Pd(dppf)Cl2-catalyzed conversion of 135 successfully afforded alkenylstannane 136, one of the precursors in the formation of 137 (Scheme [30]).

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Scheme 30

The ‘9-MeO-9-BBN variant’ of the Suzuki reaction was employed for the construction of intramolecular coupling precursor 143, the key coupling partner for the total synthesis of amphidinolide X (144).[114] Amphidinolide X is a member of the marine dinoflagellates of the genus Amphidinium sp. This species lives in symbiosis with the Okinawan­ flatworm Amphiscolops spp. and exhibits potent cytotoxic activity against various cancer cell lines. Moreover, 144 was the first example of a natural product containing a macrodiolide ring that embodies a diacid and a diol subunit rather than two hydroxy acid entities.[115] Alkyl­ iodide 142 was treated with tert-butyllithium at –78 °C, then excess 9-MeO-9-BBN was added to afford the corresponding borate 141. The latter then transferred its functionalized alkyl group to the organopalladium species derived from alkenyl iodide 140, and thus afforded product 143 in 74% isolated yield (Scheme [31]).

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Scheme 31

Diazonamide A (150), an important member of the diazonamide family, is a potent antimitotic agent exhibiting low nanomolar GI50 values towards a diverse panel of human cancer cell lines.[116] Owing to its extremely complex molecular framework, its structure was misassigned in the original isolation report. This was later corrected by Harran and co-workers in 2001 following a seminal synthesis of the nominal structure.[117] MacMillan and co-workers devised[118] a synthetic strategy that included the Suzuki coupling of boronic ester 145 and iodophenol 146 using catalytic Pd(dppf)Cl2 to yield the biaryl 147 in 82% yield. Compound 147, after few steps, afforded precursor 148. A successful tandem borylation and annulation of 148 took place upon treatment with bis(pinacolato)diboron, potassium fluoride, and Pd(PPh3)4 in a 5% aqueous solution of dioxane under microwave heating at 120 °C and yielded the desired biaryl moiety of the macrocycle 149 in 50% yield. A spectroscopic examination suggested that this reaction proceeds through rapid and selective borylation of the aryl bromide, followed by a slower coupling of the nascent boronate and the aryl triflate.[119] After two further steps, compound 149 afforded diazonamide A (150), completing a linear sequence of 20 steps in 1.8% overall yield (Scheme [32]).

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Scheme 32

Recently, the total synthesis of plakortide E was reported, and involved the application of a novel palladium-catalyzed approach towards 1,2-dioxolanes as well as an alternative substrate-controlled route leading exclusively to highly substituted 1,2-dioxolanes.[120]

Spiniferin-1 (154), with its 1,6-methano[10]annulene structural unit, was the first-known planar-chiral natural product with the [10]annulene structural skeleton. It was isolated by Cimino et al.[121] from the Mediterranean sponge Pleraplysilla spinifera. Marshall and Conrow reported the first total synthesis of racemic spiniferin-1 and confirmed its planar structure.[122] Tian’s research group[123] also reported a concise and efficient total synthesis of racemic spiniferin-1, but were unable to establish its stereochemistry. In order to determine the absolute stereochemistry of spiniferin-1 and also to study the biological activities of each of the enantiomers, efforts were made to synthesize both the enantiomers of spiniferin-1. The first total synthesis of (+)- and (–)-spiniferin-1 was accomplished by utilizing a palladium-catalyzed β-hydride elimination reaction as a key step.[124] The synthesis involved the optically active intermediates 152a and 152b (151 [125] was prepared by Robinson annulation), which were directly converted into (S)-153a and (R)-153b in high yields via Pd(PPh3)4-catalyzed β-hydride elimination of the allylic alcohol esters. The dienones (S)-153a and (R)-153b were individually converted into 154a and 154b, the two enantiomers of spiniferin-1 (Scheme [33]).

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Scheme 33

# 5

Palladium-Mediated Synthesis of Amino Acids­ and Peptides

The algal metabolites domoic acid and the isodomoic acids are causative agents of amnesic shellfish poisoning.[126] Extensive toxicological studies in both humans and marine animals revealed that domoic acid exerts its effects by binding to the kainate subfamily of ionotropic glutamate receptors.[127] A combination of stannylcupration and palladium-catalyzed coupling was utilized to accomplish the first total synthesis of three members of the isodomoic acid family (Scheme [34]).[128]

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Scheme 34

Celogentin C (163) is a bicyclic nonribosomal peptide, isolated from the seeds of Celosia argentea, that possesses inhibitory activity against tubulin polymerization. Its highly constrained structure is probably assembled in vivo from a much simpler linear peptide precursor through a series of enzymatic oxidative cross-links.[129] Inspired by the simple but powerful transformations found in nature, Chen and Feng[130] developed a synthetic strategy to construct celogentin C that included stereoselective activation of the β-C–H bond of Leu moiety 160a followed by coupling of the derived C–Pd species with the Trp partner[131] 161a to afford 162a. This is a model study for the synthesis of portion 162b of the celogentin C (163). The iodotryptophan precursor 161b, when reacted with 160b using palladium(II) acetate and silver acetate in tert-butanol afforded 162b in 85% yield with complete diastereoselectivity. The desired natural product 163 was obtained from 162b in several steps (Scheme [35]).

Complestatin (166), isolated from Streptomyces lavendulae, is an inhibitor of the alternate pathway of human complement.[132] It is also active against HIV gp120-CD4 binding and displays cytopathic effects.[133] In their total synthesis of complestatin, Boger and co-workers[134] used an intramolecular Larock cyclization [Pd(OAc)2, DtBPF, Et3N, toluene–MeCN (1:1), 110 °C] of 164 to provide 165 (56%) as a single atropisomer (>20:1) possessing the natural R-configuration (Scheme [36]).

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Scheme 35
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Scheme 36

# 6

Palladium-Mediated Synthesis of Terpenoids

Palladium-catalyzed reactions have been employed in the total synthesis of several terpenoids, including salvinorin A, (+)-8-epi-xanthatin, enokipodins A and B, (+)-carissone, ent-heliespirones A and C, (+)-heteroplexisolide E, and (±)-pestalotiopsin A, some of which possess interesting biological properties and complex molecular structures.[135]

The non-isoprenoid sesquiterpene (–)-kumausallene 169 possesses a dioxabicyclo[3.3.0]octane core moiety along with a bromoallene moiety. There are several reports describing the synthesis of kumausallene.[136] The complex dioxabicyclo[3.3.0]octane core was constructed by either an elegant ring-expansion annulation strategy or an acyl radical cyclization. Though the reaction efficiently afforded high stereoselectivity for the formation of both tetrahydrofuranyl rings, two diastereomeric bromoallenes were produced in a 1:2.5 ratio. In 2011, Tang and Werness reported[137] the first diastereo- and enantioselective total synthesis of (–)-kumausallene employing a palladium-catalyzed cascade reaction to construct the 2,5-cis-substituted tetrahydrofuranyl ring system of 168. The reaction of known C 2-symmetric diol 167 [138] in the presence of a catalytic system comprising palladium(II) chloride, copper(II) chloride, carbon monoxide, sodium acetate and acetic acid provided the bicyclic lactone 168 in 87% yield as a single stereoisomer; a few additional steps afforded (–)-kumausallene (Scheme [37]).

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Scheme 37

Schindilactone A (172),[139] a nortriterpenoid isolated from the plants of the Schisandraceae family,[140] is used for the treatment of rheumatic lumbago and related diseases and possesses biological activities for inhibiting hepatitis, tumors and HIV-1, among others.[141] The molecular architecture of schindilactone A consists of a highly oxygenated framework having 12 stereogenic centers, eight contiguous chiral centers located in the F-G-H tricyclic ring system, and an oxa-bridged ketal. Palladium-catalyzed carbonylative annulation has been successfully utilized as one of the key steps for its total synthesis.

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Scheme 38

In their approach to synthesizing the diterpenoids pallambins C and D (177), Wong and co-workers successfully employed a thiourea-and-palladium-catalyzed carbonylative annulation as a key cyclization step to assemble the furyl bicyclic lactone.[142] Both of the natural products possess a [6,5,5,5] tetracyclic skeleton having seven contiguous stereogenic centers and a triene moiety.[143] The optimized conditions involved palladium(II) acetate, copper(II) chloride, 1,1,3,3-tetramethylthiourea (TMTU)�, carbon monoxide, ammonium acetate, propylene oxide (PO) and tetrahydrofuran and were employed to effectively assemble the crucial bicyclic lactone moiety in 176 (Scheme [39]). This, after a few steps, afforded both isomers of 177 in 38 linear steps starting from (±)-Wieland–Miescher ketone (174).[142]

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Scheme 39

The first total syntheses of the bicyclic sesquiterpenoids drechslerines A and B were reported by Hagiwara et al.,[144] who utilized a palladium-catalyzed conjugate reduction and carbon monoxide insertion as one of the key steps.

The polyphenolic arene terpenoids angelicoin A (186), hericenone J (187a) and hericenol A (187b), possessing cytotoxic, antibiotic, antifungal, antioxidant, anti-inflammatory and antimicrobial activities, were isolated from the roots of pleurospermum angelicoides, fruiting body of the edible mushroom Hericium erinaceum, and a fungus of Stereum sp., respectively.[145] Barrett and co-workers[146a] made use of the palladium-catalyzed migration of the allyl moiety for the synthesis of these three natural products. The Pd(Ph3P)4 and cesium carbonate catalyzed decarboxylation of diketo esters 179 and 180, prepared from dioxinone 178, individually gave the intermediates 181 and 182. In the case of 179, a side product, dioxinone 183, was obtained in only 10% yield, and in the presence of cesium carbonate, the geranyl ester 180 was completely decomposed to the starting material. The palladium(0)-catalyzed geranyl migration seems to be significantly slower than the corresponding reaction of the simpler prenyl moiety and required several hours at room temperature. The intermediates 181 and 182, after a few more steps, afforded the natural products 186 and 187a,b using the common strategy with overall yields of 33, 24 and 21%, respectively (Scheme [40]).

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Scheme 40

Another total synthesis of angelicoins A (186a) and B (186b) from 2,2,6-trimethyl-4-dioxinone (178) and keto ester 188, respectively, was reported by the same research group.[146b] A one-pot palladium(0)-catalyzed deallyation, decarboxylation, ketene trapping, and aromatization of the diketo ester dioxinone 179c, prepared from 188, afforded the desired resorcylate 189 in 45% yield over three steps. Intermediate 182 was prepared using a similar palladium-catalyzed decarboxylative prenylation of 179b in a one-pot sequence as the key step. Both compounds 182 and 189 individually afforded angelicoins A and B after a few more steps.

The unusual diterpenoids known as taiwaniaquinoids contain a benzylic quaternary stereogenic center and possess biological activities including antitumor activity.[147] Recently, Hartwig and co-workers[148] reported an enantioselective total syntheses of (–)-taiwaniaquinone H (193) and (–)-taiwaniaquinol B (194) using a palladium-catalyzed asymmetric R-arylation strategy. The reaction of aryl bromide 190 with the 2-methylcyclohexanone derivative 191 in the presence of combined Pd(dba)2 and (R)-difluorophos as catalyst (10 mol%) afforded (R)-aryl ketone 192, the crucial intermediate for the total synthesis of 193 and 194, in 80% yield with 94% ee (Scheme [41]).

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Scheme 41

Ray and Ray utilized[149] a simple and straightforward palladium-catalyzed intramolecular Heck reaction approach for the synthesis of the sesquiterpene natural products (±)-β-cuparenone, (±)-cuparene and (±)-herbertene.[150] The intramolecular cyclization reaction of 196 (prepared from indium-mediated methallylation of 1-bromo-2-methylprop-2-ene with bromoaldehyde 195) using 2 mol% of palladium(II) acetate, 0.5 equivalent of triphenylphosphine, and 1.5 equivalent of sodium carbonate in N,N-dimethylformamide at 80 °C for five hours afforded 197 in 70% yield. This key intermediate then yielded (±)-β-cuparenone (198) in one step[151] (Scheme [42]).

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Scheme 42

Davanone (201), the principle component of davana oil, was first isolated from Artemisia pallens. [152] The sesquiterpene davanone exhibits antifungal and antispasmodic properties.[153] In 2009, Vosburg and co-workers[154] reported a synthetic strategy beginning with the known epoxy alcohol, available from geranyl acetate via allylic hydroxylation and Sharpless asymmetric epoxidation.[155] The prediction that the inherent diastereofacial preference of 199 would be to form trans-200 rather than the desired cis-configured product[156] prompted them to carry out the reaction with a range of chiral catalysts and reaction conditions. Pd2(dba)3, in combination with (S)-C3-tunePhos,[157] was found to be effective in overcoming the substrate’s diastereofacial bias and favored the formation of cis-davana acid ethyl ester 200 (Scheme [43]).

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Scheme 43

# 7

Miscellaneous Natural Products

Paucifloral F (207) is a polyphenolic natural product which potentially provides health benefits such as anti­aging/life extension and cancer prevention.[158] The Yang research group planned[159] to synthesize paucifloral F via α-arylation of the corresponding indanone 204 with 4-bromoanisole utilizing a strategy which could allow convenient introduction of structural diversity at the α-position of the indanone core. The reaction using catalyst Pd2(dba)3 with 1,1′-bis(di-tert-butylphosphino)ferrocene (DtBPF) as ligand was found to be superior. It was also observed that a reduced amount of base and a lower reaction temperature minimize the formation of the byproduct 206 to give the desired product 205 in good yield. The arylation reaction proceeded with excellent stereoselectivity and only the trans isomer was obtained. The bulky 3,5-dimethoxyphenyl group at the β-position of the indanone ring may account for the stereochemical result of the α-arylation. The amount of base employed is crucial as excess base in the reaction medium led to the second enolation of the indanone coupling product. Compound 205, upon boron tribromide catalyzed dealkylation, afforded the desired natural product paucifloral F (207) in 49% yield (Scheme [44]).

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Scheme 44

Sarpong and Jeffrey[160] demonstrated a novel palladium-catalyzed cascade reaction that provided the carbon framework of several resveratrol-derived natural products. Starting from two readily accessible building blocks, they were able to synthesize potential precursors of a large family of natural products,[161] including quadrangularin A, parthenocissin A and pallidol.

In an attempt to construct the key vicinal quaternary carbon­ stereocenters that are found in bioactive natural products such as the hyperolactones A–C and (–)-biyouyanagin A,[162] Xie and co-workers[163] employed a novel synthetic strategy using palladium-catalyzed asymmetric allylic alkylation and successfully synthesized hyperolactone C (212) and (–)-biyouyanagin A (214) in 85 and 39% yields, respectively. β-Keto ester 209 was treated with ligand (R,R)-215 (3 mol%) and Pd2(dba)3·CHCl3 (1 mol%) in the presence of isoprene monoepoxide 210. Upon quenching the reaction within 10 minutes at room temperature, the desired product 211 was isolated in 66% yield along with a side product in 31% yield. Product 211 was unstable at room temperature and slowly underwent lactonization to form hyperolactone C (212). This lactonization process was significantly accelerated by treatment with a catalytic amount of p-toluenesulfonic acid in dichloromethane for one hour. Furthermore, ent-zingiberene (213)[164] was prepared according to the procedure reported by Nicolaou et al.[162] and, upon reaction with 212, afforded (–)-biyouyanagin A (214) in 39% yield (Scheme [45]).

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Scheme 45

Palladium-catalyzed Suzuki-type couplings between an arene boronate and iodinated cyclohexenes were utilized for the total synthesis of alternaria toxins such as altenuene[165] and isoaltenuene. These were isolated from infested fruits, and show cytotoxic effect and activity towards HeLa cells (ID50 = 0.5–28 μg/mL).[166]

Kato’s research group developed[167] asymmetric syntheses of the natural products (+)-annularin G and (–)-annularin H, isolated from the organic extracts of the freshwater fungus Annulatascus triseptatus,[168] by the application of bis(oxazoline)–palladium(II)-catalyzed carbonylation of homopropargyl alcohols.

Willis and co-workers demonstrated[169] palladium-catalyzed aryl-carbonylation reactions that employed O-enolates as intramolecular nucleophiles and they exploited this reactivity to transform α-(o-haloaryl) ketones into the corresponding isocoumarins. This methodology was successfully utilized to achieve a short synthesis of thunberginol A (220), a biologically active natural product having antimicrobial, antiallergic, antidiabetic and anticancer activities.[170] The key carbonylative cyclization precursor, aryl ketone 217, was prepared by a palladium-catalyzed α-arylation of 3,4-dimethoxyacetophenone (216) with aryl iodide 218 (Scheme [46]). The isocoumarin-forming step was performed using standard conditions [Pd2(dba)3, DPEphos, Cs2CO3, toluene, 110 °C] under balloon pressure of carbon monoxide to give isocoumarin 219 in 64% yield. The natural product 220 was obtained from 219 in 98% yield[171] by cleavage of the ether linkage with boron tribromide.

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Scheme 46

Among a class of ecologically significant substances, the furofurandione metabolites avenaciolide (226a) and epiethisolide (226b) are biologically important as they inhibit the growth of other fungi to enable the host species to compete successfully.[172] Hon and Chen successfully employed[173] palladium-catalyzed epimerization of the γ-alkenyl substituent of the bislactones to achieve the synthesis of avenaciolide and epiethisolide. The endo-hydroxylactone­ 221, prepared from the reaction of cyclopentadiene with glyoxylic acid, afforded compounds 223 and 224 (Scheme [47]). When 223 was treated with a catalytic amount of palladium(II) acetate in the presence of triphenylphosphine in tetrahydrofuran at room temperature, the exo-epimer 227 (E,E) was obtained in 62% yield as a sole product. Presumably, the initially formed π-allyl–palladium intermediate underwent isomerization to a more stable form followed by recyclization. During this process, the diene moiety also isomerized to the more stable E,E form. Vinyl bromide 224 also underwent palladium-catalyzed epimerization to give the exo-isomer 225, also E-configured, in 87% yield. Compounds 227 and 225 afforded avenaciolide (226a) and epiethisolide (226b), respectively, after a few additional steps.[173]

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Scheme 47

Lithospermic acid was isolated from the roots of Lithospermum ruderale [174] and possesses inhibition properties of adenylatecyclase and an antioxidizing low-density lipoprotein.[175] Hwu and Varadaraju reported[176] an asymmetric total synthesis of (+)-lithospermic acid and established the C10 R stereogenic center of lithospermic acid by a chemical method. Moreover, the palladium-catalyzed dynamic catalytic asymmetric transformation (DYKAT) cyclization allowed an efficient approach to the one chiral center present in (+)-hippospongic acid A.[177]

Isobongkrekic acid (235a) and bongkrekic acid (235b) are poisonous antibiotics produced by Pseudomonas cocovenenans (also called Burkholderia gladioli). They are also found in contaminated coconuts that can cause food poisoning.[178] Moreover, both 235a and 235b inhibit adenine nucleotide translocase, which mediates the ADP–ATP exchange in mitochondria.[179] These effects on mitochondria have been shown to delay the programmed cell death.[180] As a result, bongkrekic acid derivatives have become general tools for the elucidation of apoptosis mechanisms. Ley and co-workers utilized[181] a combined palladium-catalyzed Stille–Migita coupling[4] [182] and Sonogashira[4] reaction for the total synthesis of 235a and 235b. For this purpose, compounds 228 and 229 were individually prepared from homopropargyl bromide and (S)-2-methylbutane-1,4-diol, respectively. The Stille–Migita coupling of the fragments 228 and 229 under the reaction conditions [Pd(PPh3)4, copper thiophene-2-carboxylate, Ph2PO2NBu4, Et3N] afforded a 3:2 mixture of isomers 230a and 230b in 75% yield. These were easily separated by conventional chromatography. Increasing the amount of triethylamine at the end of the reaction efficiently afforded an equilibrium 3:1 mixture. By this method, the required E,E-diene 230a was isolated in an acceptable 60% yield. Compound 230a afforded the fragment­ 231 after a few more steps. The reaction of 231 and 232 (prepared from α-hydroxyacetone) with Pd(PPh3)2Cl2, copper(I) iodide and triethylamine in tetrahydrofuran afforded the desired enynes 233a and 233b in 53% yield along with the dimer 234 that resulted from a Glaser coupling.[183] The use of triethylamine as both base and solvent proved to be effective, as the dimer product formation was significantly reduced to give a product mixture containing a 74% yield of the eneynes 233a and 233b. This mixture afforded, after a few steps, 235a and 235b in 35 and 17% yields, respectively (Scheme [48]).

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Scheme 48

Neooxazolomycin, a potent antibacterial, antiviral, and in vivo antitumor-active agent, was synthesized by a combined palladium-catalyzed enolate alkenylation and Stille coupling reaction as key steps.[184]

A consise total synthesis of vitamin E was developed by Tietze et al.[185] using an enantioselective domino Wacker–Heck process as the key reaction step leading to the formation of the chroman framework with the necessary R-configuration at the stereogenic center with 97% ee.

1α,25-Dihydroxyvitamin D3 (239) is a hormonally active metabolite of the seco-steroid vitamin D3, interacts with the vitamin D nuclear receptor[186] and controls mineral homeostasis and a multitude of cellular processes including differentiation, antiproliferation, growth, apoptosis, angiogenesis, and immunomodulation.[187] Mourino and co-workers described[188] an aqueous tandem palladium-catalyzed ring closure and Suzuki coupling reaction of 237 and 238 to synthesize the triene system of the natural hormone, 239. Treatment of a mixture of 237 and 238 in aqueous potassium phosphate and tetrahydrofuran with a catalytic amount of Pd(PPh3)2Cl2 at room temperature for one hour afforded 239 in 81% yield after a standard desilylation process (Scheme [49]). The reaction was greatly affected by the presence of excess of one or the other synthetic building block, exclusion of moisture, and/or elevated temperature.

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Scheme 49

The kinamycins are complex bacterial metabolites having broad-spectrum anticancer and antimicrobial activities.[189] They also possess submicromolar inhibitory potencies against over 60 different cancer cell lines and both Gram-positive and Gram-negative bacteria. It is assumed that the biological activity of kinamycins arise from reductive cleavage of DNA.[190] The complex structure and interesting biological activities have led several research groups to carry out the total syntheses of kinamycins, including kinamycin F (243).[191] Herzon and co-workers accomplished[192] a short synthesis of 243 utilizing a palladium-catalyzed Heck reaction as the key ring-forming step (Scheme [50]).

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Scheme 50

A palladium catalytic system that allowed for the direct arylation and vinylation of imidazolinone under mild conditions was developed by Chen and co-workers. With this methodology, dibromophakellstatin was synthesized in 40% overall yield.[193] An enantioselective synthesis of the tricyclic core of the immunosuppressant natural product (–)-FR901483 was reported. A palladium-catalyzed [Pd2(dba)3, Xantphos, KOPh] intramolecular enolate alkenylation reaction was used as the key ring-forming step for the construction of the bicyclo[3.3.1]azanonane ring system.[194]

A palladium-catalyzed DYKAT reaction of an amine with two equivalents of butadiene monoxide was used to construct trans- and cis-2,5-dihydropyrroles, the key intermediate for the total synthesis of (2R,3R,4R,5R)-2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine [(+)-DMDP], (–)-bulgecinine, and (+)-broussonetine G.[195] Trost and O’Boyle, in another approach, synthesized[196] 7-epi-(+)-FR900482 and tested its biological activities, which demonstrated equal potency against several cancer cell lines relative to the natural product. The palladium-catalyzed DYKAT methodology and an intramolecular Heck reaction were utilized as key steps in obtaining this equipotent epimer in excellent yield. FR900482 is a potent anti-tumor therapeutic agent used as a replacement candidate for the clinically useful mitomycin C. The biological activities and structural properties of FR900482 were studied extensively, and several total and formal syntheses were developed.[197] [198] The shortest route was reported by Williams[197] using 29 linear steps (33 total). A palladium-catalyzed DYKAT reaction[199] of divinyl carbonate 245 and phthalimide (244) gave amino alcohol 246 as a single stereoisomer; seven further steps afforded the aziridine 247. The Heck coupling of 249 (prepared in a few steps from aziridine 247) furnished the exocyclic olefin 250 en route to the natural product 251 (Scheme [51]). No double-bond isomerization was detected in this step, even though such a process would lead to aromatization, via formation of an indole.

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Scheme 51

It is reported that the stereochemistry at C7 of FR900482 is lost prior to alkylation of DNA.[200] Therefore, the synthesized epimer of natural product FR900482 possesses comparable activity and is capable of cross-linking DNA, as both 7-epi-FR900482 and the natural product itself reach a common intermediate prior to alkylation. Their synthesis requires only 23 linear steps (29 total) resulting in 1.4% overall yield from commercially available hexa-1,5-diene-3,4-diol.

A palladium-catalyzed Stille coupling was employed as a key coupling step in the short syntheses of the epoxyquinone natural products SDEF 678 metabolite and speciosins C (255), A (256) and B (257). The speciosins,[201] containing an epoxide ring, were isolated from the Chinese fungus Hexagonia speciosa. The palladium-catalyzed coupling of a halogen-substituted 1,4-benzoquinone monoketal 252 with alkynyl stannanes 254a and 254b afforded the coupling products 253a and 253b, respectively. These, after a few steps, provided compounds 255–257 in good yields (Scheme [52]).[202]

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Scheme 52

Willis and co-workers developed[203] a tandem palladium-catalyzed aryl and alkenyl carbon–nitrogen bond formation to construct a variety of indoles bearing sterically demanding nitrogen substituents, including the natural product demethylasterriquinone A.[204] Tietze et al. reported[205] a new application of a domino Tsuji–Trost–Heck–Mizoroki reaction in the synthesis of the structural core of tetracyclines. These natural products represent a very important group of antibiotics.[206]

Pentosidine, a biologically important, advanced glycation end-product, was accessed in a rapid, high-yielding manner. The synthesis was accomplished via a six-step sequence starting with 3-amino-2-chloropyridine and featured a palladium-catalyzed tandem cross-coupling and cyclization to construct the imidazo[4,5-b]pyridine core. Pentosidine is a naturally occurring biological fluorophore and, as such, has found use in noninvasive diagnostics. It has been reported as a chemical marker of diabetic complications, kidney dysfunction, oxidative stress, aging, and age-related diseases.[207]


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Conclusion

Since their discovery, palladium-catalyzed reactions have been employed as central strategic steps in total syntheses of a number of natural products. As evidenced by its prevalence in the literature, the incorporation of palladium reactions into synthetic schemes frequently makes synthetic manipulations facile and concise. This comprehensive review presents the use of palladium-mediated cyclization reactions in natural products synthesis. These reactions are excellent tools for stereo- and regioselective steps in the syntheses of various biologically active natural products. Although both ring-forming and coupling reactions mediated by palladium reagents have been applied in approaches to a wide range of targets presented here, many more challenges remain to be solved through further exploration of palladium chemistry.


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Acknowledgement

We are thankful to UGC (K.C.M. to New Delhi for a UGC Emeritus Fellowship) and CSIR (B.S. to New Delhi for a Senior Research Fellowship).



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