Regioselective palladium-catalysed cross-coupling reactions: a powerful synthetic tool

Abstract

The purpose of this review is to highlight the powerful nature of palladium-catalysed regioselective (site-selective) cross-coupling reactions for facilitating the synthesis of biologically important natural products as well as certain industrially relevant drugs. A total of 28 natural products have been included to highlight the potential of this methodology.

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Anant R. Kapdi

Anant Kapdi was born in Mumbai, Maharashtra, India, in 1980, and studied chemistry at the University of Mumbai (MSc 2002) and York (MSc 2005; Prof. Ian J. S. Fairlamb). He completed his PhD in 2008 under the supervision of Prof. Fairlamb at The University of York, before starting postdoctoral work as an Alexander von Humboldt Fellow in the research group of Prof. Lutz Ackermann at the Georg-August-University, Gottingen. He returned to India in 2010 and was appointed as DST-SERC Fast Track Fellow (2011) and DST Inspire Faculty (2012) at the Institute of Chemical Technology before taking up UGC-FRP Assistant Professor position (2014). The unifying theme of his research program is the development of synthetically efficient processes using novel metallacycles and their application towards the development of potent palladium-based anticancer drugs.

Dharmendra Prajapati

Dharmendra Prajapati was born in Mumbai, Maharashtra, India, and studied chemistry at the University of Mumbai (MSc 2010). Currently he is pursuing his Ph.D. studies under the guidance of Dr Anant R. Kapdi on the application of novel water soluble metallacyclic complexes for addressing regioselectivity issues in metal-mediated cross-coupling reactions.

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1 Introduction

Palladium-catalysed cross-coupling reactions are one of the most powerful C–C bond forming technologies that have found applications ranging from the synthesis of simple molecules, functional materials, synthetic intermediates as well as a large number of biologically active molecules.^1–3 The importance of these reactions has increased tremendously due to the simplicity, generality and mildness of the protocols made possible through the rapid development of highly active ligands (used in combination with a palladium precursor) and palladium complexes.⁴ Total synthesis of naturally occurring molecules is one of the areas that has benefited immensely with palladium-catalysed cross-coupling reactions playing a central role in developing efficient synthetic routes to access such ubiquitous molecules.⁵

For accessing these structurally diverse molecules the commonly applicable palladium-catalysed cross-coupling reactions such as Suzuki–Miyaura,⁶ Heck,⁷ Sonogashira,⁸ Negishi,⁹ Stille¹⁰ and Tsuji–Trost allylation¹¹ have been employed as one of the key features of the synthesis. Regioselective cross-coupling is one aspect of these reactions that has largely contributed towards their application in synthesis. In this review we therefore intend to highlight the capability of palladium-catalysed cross-coupling reactions towards addressing the problem of regioselectivity leading to the synthesis of a variety of natural products and pharmaceutical drug intermediates. A total of 28 naturally occurring molecules and one drug molecule have been incorporated to highlight the potential of this methodology. The choice of the examples is primarily based on the importance of the natural product in question as well as the potential applicability of the synthetic strategy employed towards the synthesis of such complex molecules.

2 Regioselective cross-coupling reactions

Regioselectivity in palladium-catalysed cross-coupling reactions is attributed to the selective activation of C–X bonds in polyhalogenated heteroaryl compounds. Most of the naturally occurring compounds possess heteroaryl as the central structural motif that could be functionalised selectively by taking into account the difference in reactivity of C–X bonds. An excellent review highlighting these aspects in general cross-coupling reactions for polyhalogenated heteroaryl compounds was recently reported by Fairlamb.¹² The review also sheds light on the involvement of oxidative addition as the intrinsic step for the regioselectivity in such reactions. NMR spectroscopic¹³ and theoretical studies¹⁴ also provide evidence for this claim helping to predict regioselectivity for a variety of polyhalogenated heteroaryl compounds although this is not the focus of this review.

Our focus is to bring in front of the readers the synthetic application of such powerful C–C bond forming reactions which are governed by several factors such as electronic and steric effects, influence of functional group in proximity of the coupling site etc. These could also be influenced by the choice of palladium complex and the coupling conditions to suit the type of regioselectivity desired in the cross-coupling reactions. Several such examples of regioselective cross-coupling of polyhalogenated compounds have been reported in literature¹² and will act as the good starting point for their application towards the synthesis of a variety of naturally occurring compounds.

2.1 Suzuki–Miyaura cross-coupling

Imidazoles are important heterocyclic structural motifs that have found a lot of interest due to their occurrence as marine alkaloids exhibiting a wide variety of biological properties such as antibacterial and anticancer. In recent years several such alkaloids bearing the imidazole moiety have been isolated and structurally characterized.¹⁵ One such set of molecules that has attracted the attention of scientists are the Nortopsentins A–C (1a–c) & D (synthetic analog 1d) which exhibit a characteristic 2,4-bisindolylimidazole skeleton (revealed after thorough characterization of the compounds isolated from a marine sponge Spongosorites ruetzleri).¹⁶ The cytotoxic and antifungal properties of these molecules have contributed largely towards developing an efficient synthetic route which was first put forth by Ohta and co-workers in 1996 (Scheme 1).¹⁷

Scheme 1 Regioselective synthesis of Nortopsentins C & D via palladium-catalysed Suzuki–Miyaura cross-coupling.

The synthesis of Nortopsentins A & B (1a & 1b) was carried out using straight forward synthetic transformations. However, for the synthesis of Nortopsentin C & D (1c & 1d), regioselective Suzuki–Miyaura cross-coupling of polyhalogenated imidazole moiety with protected indole-3-boronic acid served as the key step towards achieving the desired target. Although, the selectivity observed in both the cases was high, reactivity suffered drastically in case of regioselective step leading to Nortopsentin C 1c.

Indoloquinolines framework has in recent years attracted lot of attention as potential drug discovery candidates with several bioactive molecules being isolated from a West African climbing shrub Cryptolepis Sanguinolenta and other related shrubs.¹⁸ Recently Timari and co-workers reported¹⁹ the isolation of a series of tetracyclic indoloquinoline compounds from C. Sanguinolenta namely: Cryptolepine and Quindoline,¹⁸ Cryptosanguinolentine and Cryptotackeine.²⁰ Besides the fact that these and similar other indoloquinoline compounds isolated from C. Sanguinolenta have exhibited promising antibacterial, anti-inflammatory and antiplasmodial activity, it is the anticancer activity of certain compounds such as quindoline (2) that prompted Timari and co-workers to also develop possible synthetic route for accessing such molecules (Scheme 2).¹⁹ For the construction of the indoloquinoline structural motif a regioselective Pd(0) catalyzed Suzuki–Miyaura cross-coupling between 2,3-dibromoquinoline and protected 2-aminophenyl boronic acid was envisaged as the most efficient approach. Selective activation of C–Br bond in the 2^nd position on the quinoline ring provides the arylated product in decent yields albeit with very high regio-control which was later conveniently converted into the alkaloid Quindoline (2).

Scheme 2 Regioselective Suzuki–Miyaura cross-coupling for the synthesis of Qindoline.

Similar to indoloquinolines, the bis(indole)pyrazines are another class of secondary metabolites which due to their biological importance²¹ also warrants the search for more efficient synthetic routes. Dragmacidin D (3) is one such secondary metabolite possessing the bis(indole)pyrazine structural motif and was isolated from a deep-water sponge Spongosorites by different research groups.^22,23 A wide spectrum of biological and pharmacological activity²⁴ exhibited by Dragmacidin D (3), has largely contributed towards the development of synthetic strategies^25,26 to obtain such an important molecule. One such strategy leading to the synthesis of an advanced fragment (3a) for Dragmacidin D (3) was put forward by Jiang and co-workers (Scheme 3).^26a

Scheme 3 Synthesis of advanced fragment for Dragmacidin D (3) using regioselective Suzuki–Miyaura cross-coupling.

The sequential implementation of palladium(0) catalyzed Suzuki–Miyaura and Stille cross-coupling reactions was presented as the key feature for the construction of the natural product skeleton. For the installation of the first fragment towards Dragmacidin D (3), a regioselective Suzuki–Miyaura cross-coupling between 3,6-dibromopyrazine and protected indole-3-boronic acid was performed to give the product in good yields with very high selectivity towards the activation of C–Br bond in the 6-position of the pyrazine ring.

Lamellarins are another important series of natural products possessing a 3,4-diarylpyrrole structural motif that has been isolated from a variety of different natural sources such as marine prosoblanch mollusk, ascidians and sponges.²⁷ Lamellarins like several other structurally related natural products have exhibited unique and useful biological activity ranging from cytotoxic activity to HIV chemotherapeutic activity.²⁸ Several research groups have been active in developing synthetic methodologies towards the synthesis of these natural products.²⁹ Lamellarin G trimethyl ether (4) is one such natural product that has found large amount of attention with the first synthesis being reported by Steiglich via an interesting Pd(0)-mediated decarboxylative cyclisation reaction.^29a Few others have also attempted to synthesise Lamellarin G trimethyl ether via the incorporation of a regioselective Suzuki–Miyaura cross-coupling as the key step.³⁰

First of these was reported by Iwao and co-workers in 2003 where the first step towards Lamellarin G trimethyl ether involved a highly regioselective Pd(0)-catalysed Suzuki–Miyaura cross-coupling between a ditriflate of N-alkylated pyrrole with 3,4-dimethoxyphenyl boronic acid leading exclusively to the 4-arylated pyrrole (Scheme 4).^30a This was subsequently converted into another natural product Ningalin B 4a (premethylated) which was further transformed into 4.

Scheme 4 Lamellarin G trimethyl ether (4) synthesis via permethylated Ningalin B using regioselective palladium-catalysed Suzuki–Miyaura cross-coupling.

Recently, Handy and co-workers during their study of the effect of solvent on the regioselectivity in Suzuki–Miyaura cross-coupling of dihalopyrroles, observed that change in solvent brought about a complete reversal in the regioselectivity (Scheme 5).^30b This methodology was later applied towards the total synthesis of Lamellarin G trimethyl ether (4) via regioselective Suzuki–Miyaura cross-coupling of 2,4-dibromopyrrole with aryl boronic acid with the best selectivity being observed in the case of PhMe–EtOH solvent mixture. Although the intermediate was not isolated and subsequently converted in situ by the reaction with 3,4-dimethoxyphenyl boronic acid to the 3,4-diarylatedpyrrole product. The authors hypothesize the regioselectivity at C-5 position to be due to the nitrogen on pyrrole to direct insertion of palladium at the C-5 position which is favoured in PhMe–EtOH system than DMF.

Scheme 5 Alternate synthesis of Lamellarin G trimethyl ether.

Pyridine derivatives particularly 2,4-disubstituted pyridines have found wide applications as possible pharmaceutical drug candidates or natural products with useful biological activities.³¹ To access such diversely substituted pyridines for further applications a reliable synthetic strategy would be to employ Pd(0)-catalysed regioselective reaction which is exactly what was attempted by Cid and co-workers (Scheme 6).³²

Scheme 6 Regioselective alkenylatiion of 2,4-dibromopyridine.

As a part of their study Cid and co-workers explored the possibility of achieving regioselectivity for 2,4-dibromopyridine by the employment of Pd(0)-catalysed Suzuki–Miyaura cross-coupling with alkenylboronic acid in the presence of TlOH as the base at 25 °C in THF as the solvent. The cross-coupling proceeded smoothly with alkenylation taking place predominantly in the 2-position furnishing the 2-alkenylated-4-bromopyridine in good yields. The product obtained was further subjected to Sonogashira reaction to give a key intermediate for the total synthesis of visual pigment A2E³³ (5).

Another naturally occurring compound having simple but unique diarylethane substructure is Combretastatin A-4 (CA-4), a powerful inhibitor of tubulin polymerisation, which was derived from the African bush willow Combretum caffrum.³⁴ Its property to effectively inhibit tumor growth and the antivascular effects shown by Combretastatin A-4 has allowed clinical trials to be performed for the treatment of solid and liquid tumors.^35,36

It is therefore of importance to develop more active molecules having Combretastatin A-4 substructure and with this idea in mind Tron and co-workers developed a novel regioselective Pd(0)-catalysed Suzuki–Miyaura cross-coupling reactions of dihaloheteroatoms (Scheme 7).³⁷ As a part of the study several heteroaromatic analogues of Combretastatin A-4 (6a–d) were synthesised which exhibited promising cytotoxic activity. One of the analogues 6d displayed excellent cytotoxic activity with comparable pharmacodyanamic but better pharmacokinetic profile compared to Combretastatin A-4.

Scheme 7 Regioselective synthesis of Combretastatin analogues.

Allylic systems such as prenyl(3,3-dimethylallyl) have found wide applications due to their occurrence in a variety of important natural products. Carbazole containing natural products bearing prenyl substituent form a major part and are represented by molecules such as the antibacterial Carquinostatin A (7a),³⁸ anti-TB active Micromeline (7b),³⁹ and the anti-HIV active Siamenol⁴⁰ (7c) that have been isolated from natural sources. For accessing such bio-active molecules a novel prenylation protocol was recently developed by Knoelker and co-workers (Scheme 8).⁴¹ A highly regioselective Pd(0)-catalysed Suzuki–Miyaura prenylation of bromocarbazoles was performed using prenylBpin reagent to give 3-prenylcarbazole as the exclusive product rather than the competing 3-tert-prenylcarbazole.

Scheme 8 Regioselective allylation of carbazoles using palladium-catalysed Suzuki–Miyaura cross-coupling reactions.

The allyl electrophilic partner chosen for the transformation was an unsymmetrical secondary allylic carbonate which on coupling with different aryl boronic acids furnished regioselective allyl–aryl product exhibiting excellent enantioselectivities and with completes inversion of configuration. Regioselectivity in these reactions was attributed to the unstable nature of the allyl electrophilic partner i.e. tert-prenylboronate which is unstable towards 1,3-isomerisation and forms prenylboronate. This was also confirmed by following the thermal rearrangement of tert-prenylboronate to prenylboronate by ¹H NMR spectroscopy in DMF-d₇ at 80 °C for 1 h.

Given the problems associated with palladium-catalysed prenylations of obtaining a mixture of products either via isomerisation or allyl inversion,⁴² the formation of 3-prenylcarbazole as the regioselective product certainly could prove to be an important synthetic strategy which was employed successfully by Knoelker towards the synthesis of the methylated analogues of Carquinostatin A (7a), Micromeline (7b) and Siamenol (7c).

Suzuki–Miyaura cross-coupling of allylic derivatives with different organometallic reagents has proven to be an important tool for the synthetic organic chemist, although in most cases the allyl electrophilic partners have been restricted to primary allylic halides or alcohol derivatives (few examples reported in literature).⁴³ More challenging transformation would therefore be to couple secondary allylic alcohol derivatives⁴⁴ which was recently achieved by Zhang and co-workers leading to the development of a regio- and stereoselective palladium-catalysed Suzuki–Miyaura cross-coupling protocol (Scheme 9).⁴⁵ The regioselectivity in these reactions was proposed to take place via reductive elimination from the less sterically hindered site of the π-allylpalladium complex providing the regioselective product.

Scheme 9 Naproxen (8) synthesis via regioselective Suzuki–Miyaura allylation.

This methodology was further employed towards the successful synthesis of (S)-naproxen (an anti-inflammatory drug 8) firstly through the employment of Suzuki–Miyaura cross-coupling reaction furnishing the (R)-allyl–aryl product in 82% yield and 95% ee which on oxidation and subsequent recrystallization gave the drug in 78% yield and >99% ee.

2.2 Negishi cross-coupling

One of the earliest examples highlighting the application of regioselective Negishi cross-coupling reactions was reported by Bach and co-workers for the synthesis of Cystothiazole E 9 (Scheme 10).^46,47 Cystothiazoles are a series of structurally diverse natural products with a bisthiazole structural motif as one of the unique features which was revealed by Sakagami and co-workers⁴⁸ who first isolated (from myxobacterium Cystobacter fuscus) and confirmed the structure for these molecules.

Scheme 10 Regioselective double Negishi coupling towards the synthesis of Cystothiazole E 9.

For the construction of the cystothiazole E molecule (9), simultaneous double Negishi cross-couplings of 2,4-dibromothiazole with different organozinc reagents was envisaged as the key steps in the synthetic route.⁴⁷ Complete regioselectivity was observed in both the reactions for the cross-coupling reaction to take place via activation of C–Br bond in the more electrophilic 2-position rather than the less electrophilic 4-position.

Continuing with 2,4-dibromothiazole as the electrophilic coupling partner for accessing other important natural products, Bach and co-workers developed a convergent synthetic strategy towards the total synthesis of Endothelin converting enzyme inhibitor WS 75624 A (Scheme 11).⁴⁹ WS 75624 A and WS 75624 B containing natural products with 2,4-disubstituted thiazole moiety as the central feature were isolated from Saccharothrix sp. no. 75624 in 1995.^50,51

Scheme 11 ECE inhibitor WS 75624 A 10 via regioselective Negishi coupling reaction.

As a part of the strategy the molecule WS 75624 A (10) was broken into two fragments which could be coupled together during the final stages of synthesis. To access the right hand fragment containing the 2,4-disubstituted thiazole, Bach and co-workers envisaged a novel regioselective Negishi cross-coupling reaction of the 2,4-dibromothiazole (to occur selectively at 2-position) as a possible strategy.⁴⁹ This was achieved by the in situ conversion of the silyl-protected iodoalcohol into nucleophilic organozinc reagent which was subsequently coupled with 2,4-dibromothiazole under palladium(0)-catalysed Negishi coupling conditions furnishing the cross-coupled product showing excellent regioselectivity towards coupling at 2-position of the 2,4-dibromothiazole. Such a strategy allowed the synthesis of WS 75624 A (10) to be completed in 8 steps with 45% as the overall yield obtained.

The occurrence of multi-substituted benzofurans⁵² in a wide range of natural products has attracted lot of attention in recent years also due to the ease of substitution that could be performed on the benzofuran nucleus through simple synthetic transformations. Eupomatenoids represent a diverse class of naturally occurring molecules containing multi-substituted benzofurans and were isolated from two plants belonging to the angiosperm family Eupomatiacaea.⁵³ One of the important characteristic features of the eupomatenoid is the presence of a 2,3,5-trisubstituted benzofuran (differently substituted in all 3 positions) which makes their synthesis all the more challenging. For accessing such molecules a far more aggressive synthetic approach is needed which was recently put forth by Bach and co-workers that was based on the employment of regioselective palladium-catalysed cross-coupling reaction of an easily available starting material 2,3,5-tribromobenzofuran (Scheme 12).⁵⁴

Scheme 12 Eupomatenoids (11a–g) synthesis via regioselective Negishi coupling of tribromooxazoles.

The synthetic strategy involved three consecutive C–C bond forming reactions: firstly a highly regioselective palladium-catalysed Negishi coupling at the C-2 position followed by nickel-catalysed coupling at C-5 which is probably governed by steric factors and finally the cross-coupling at C-3 position giving rise to a series of eupomatenoid analogues.

The occurrence of prenylated arenes in nature has been broadly represented by a series of natural products such as demethylmoracin, cathafuran A & B etc.⁵⁵ Siamenol (12) is one such naturally occurring bioactive molecule possessing prenylated arene as the central structural motif which was isolated from Murraya siamensis and exhibited potent anti-HIV activity.⁵⁶ One of the challenges for accessing these molecules is to develop a synthetic protocol involving the prenylation to give a linear prenylated molecule as the regioselective product.

Cheong and Buchwald recently reported a completely linear-selective Negishi cross-coupling reactions using allylzinc reagent in the presence of a palladium(II) precatalyst (in combination with different Buchwald ligands, Scheme 13).⁵⁷ The wider utility of the protocol was showcased by the concise synthesis of the naturally occurring siamenol (12) starting from 4-bromotoluene as the cheaply available starting material in 6 high yielding steps. One of the key features of the protocol was the linear-selective prenylation of substituted carbazole performed using palladium(II) precatalyst in combination with C-Phos ligand yielding the linear-prenylated product with complete selectivity. To get further insight into the regioselective nature of the prenylation reaction DFT studies were also performed that pointed towards the possibility of two main transition states namely a four-membered and a six-membered leading to α-prenyl and γ-prenyl palladium intermediates. The energetic preference in these two transition states was towards the four-membered α-prenyl palladium intermediate which exhibited lower energy and is mainly related to the high level linear-selectivity observed in such reactions.

Scheme 13 Regioselective prenylation for the synthesis of Siamenol (12).

In recent years the number of bacterial infections has increased drastically leading to an increase in demand for more effective antibiotic drugs. Investigations into the bacterial growth have revealed bacterial elongation factor EF-Tu (which acts as the enzyme essential for biosynthesis of proteins in bacteria) as the validated drug target.⁵⁸ To counter such a problem researchers have identified four different classes of compounds that could inhibit EF-Tu efficiently, namely kirromycin, enacycloxin IIa, pulvomycin and GE2270A.⁵⁹ One of the most well studied and the oldest compound isolated by Selva and co-workers from Planbispora rosea ATCC 53773 with the structure being reported subsequently in 1991 (although wrongly assigned).⁶⁰ Elusive configurational assignments were carried out by several research groups as a part of the synthetic studies performed on the different fragments of GE2270A.

Bach and co-workers were the first to report the concise total synthesis of GE2270A 13 comprising of 20 synthetic steps with an overall yield of 4.8% (Scheme 14).^61a–c For accessing the eastern fragment of GE2270A a highly regioselective Negishi cross-coupling of substituted 2,6-dibromopyridine was envisaged as the most useful leading to an important advanced fragment. As a part of the synthesis a regioselective Stille cross-coupling reaction of 2,4-dibromothiazole has also been employed to provide another fragment eventually leading to the natural product GE2270A (13).

Scheme 14 Thiazolyl peptide antibiotic GE2270A (13) via regioselective Negishi coupling.

2.3 Stille cross-coupling

In the earlier section we have seen one of the synthetic applications of regioselective Stille cross-coupling reactions towards the synthesis of thiazolyl peptide antibiotic GE2270A 13 (Scheme 14),^61a–c continuing on the same lines we now would focus on other examples that employ regioselective Stille coupling as one of the key steps.

Cho and co-workers in an attempt to develop a concise synthetic route for joubertinamine (14)⁶² and (±)crinine (15)⁶³ natural products, employed regioselective Stille coupling of 3,5-dibromo-2-pyrone with arylstannanes as the starting point (Scheme 15).⁶⁴ The reaction was found to be selective for cross-coupling to take place at the C-3 position rather than C-5 position.

Scheme 15 Synthesis of (±)crinine (15) and joubertinamine (14) via regioselective Stille coupling of dibromo-2-coumarin.

Synthetic utility of multi-substituted furans is well known and has attracted a lot of attention in recent years due to their occurrence in natural products having wide range of bioactivity.⁶⁵ Terpenoid containing multi-substituted furan containing natural products such as monoterpene rosefuran⁶⁶ and α-clausenan,⁶⁷ sesquiterpenes agassizin⁶⁸ are also known to exhibit excellent bioactivity. Rosefuran (16) in particular has a unique structure with substitutions in the 2,3-position of the furan ring. In order to gain access to such molecules a convergent synthetic strategy involving a highly regioselective Stille cross-coupling of 2,3-dibromofuran with allylstannanes was recently developed by Bach and co-workers (Scheme 16).^69a Under relatively mild conditions it was observed that the allylation took place selectively at the C-2 position of the furan bearing an acceptor substituent in the C-5 position which is in general cases the preferred site of attack in polyhalogenated furans.^69b–d C-3 position in comparison is found to be less reactive and also less preferred for attack by Pd(0). The allylated product was subsequently converted into rosefuran 16 in further 3 steps with 35% overall yield.

Scheme 16 Rosefuran (16) synthesis via regioselective Stille coupling of 2,3-dibromooxazole.

2.4 Tsuji–Trost and related allylic alkylations

In comparison to uncatalysed allylic substitution reactions which suffer from several drawbacks, Pd(0)-catalysed allylic substitution provides both high regio- and stereoselectivity.⁷⁰ In certain cases only the chemoselectivity between two different leaving groups with comparable reactivity has been investigated.⁷¹ One such report by Fairlamb and co-workers discusses a novel Pd(0)-catalysed allylic substitution reaction of difunctionalised terpenyl halides which proceeds smoothly with excellent stereo-, regio- and chemoselectivity (Scheme 17).⁷² Such a methodology would definitely be of very high synthetic utility with the possibility of employing difunctionalised allylic sesquiterpenes and monoterpenes that have proven to be important synthetic blocks.

Scheme 17 Regioselective allylation of phenols.

As a part of the study Fairlamb and co-workers efficiently coupled several difunctionalised terpenyl halides with substituted phenols via Pd(0)-mediated and base-assisted allylation reaction. This methodology was subsequently applied towards developing a possible synthetic route of one of the advanced fragments of farnesyl containing natural product Likonide B 17 (as a part of a new family of marine natural products also containing Likonide A and Avarone) from the Kenyan marine sponge Hyatella sp. by Kashman and co-workers.⁷³ The regio- and stereoselective nature of the protocol allowed the desired fragment of Likonde B 17 to be synthesised in good yields (although no formal synthesis of Likonide B 17 using this route has yet been reported).

Palladium-catalysed asymmetric Tsuji–Trost allylic alkylation is a powerful synthetic tool and has found wide applicability in natural product synthesis containing cyclohexane or cyclopentane structural motifs.⁷⁴ The allylic alkylation was generally performed on cycloalkenediols under palladium-catalysed conditions with (S)-BINAPO employed as chiral ligand for asymmetric induction.⁷⁵ The methodology was initially developed by Mori and co-workers for cyclopentenediol derivatives which underwent facile regioselective alkylation, although the enantioselectivity was found to be dependent on the type of leaving group employed (Scheme 18).⁷⁶

Scheme 18 (+)-γ-Lycorane (18) synthesis via regio- and enantioselective allylation reaction.

An asymmetric version for the cyclohexenediols was later developed employing benzyloxy group as the leaving group with (S)-BINAPO as the chiral ligand providing selective monoalkylated product in good yield with decent enantioselectivity.⁷⁷ To explore the possibility of applying the methodology towards natural product synthesis Mori and co-workers successfully demonstrated this for (+)-γ-Lycorane (18). Lycorane belongs to the class of Amaryllidaceae alkaloids⁷⁸ with several racemic synthetic routes reported in recent years. The enantioselective allylic alkylation proceeded smoothly with the selective formation of monoalkylated product that was carried forward to provide the natural product 18 in an overall 23% yield.

Pyrrolo[2,3-b]indole natural products containing prenyl or geranyl substitution are wide spread with a large number of synthetic procedures been developed to access such structural motifs.⁷⁹ Flustramine A and B are examples of this class of natural products which are known to possess muscle relaxant properties while Flustramine A has also shown voltage-gated channel blocking activity.^80a,b In an attempt to develop synthetic route for Flustramine A and B (19 & 20), Trost and co-workers recently reported a protocol for the Pd-catalysed asymmetric prenylation of oxindoles (Scheme 19).⁸¹ An interesting feature of this protocol was to afford prenylated and reverse-prenylated products with excellent regio-, enantio- and diastereocontrol.

Scheme 19 Flustramine A and B (19 & 20) synthesis via Pd-catalysed regioselective prenylation of oxindoles.

For this purpose two structurally different ligands were employed and with the judicious choice of solvents and additives the regio- and diastereoselectivity was altered to give either the branched product or a linear product. In CH₂Cl₂ as solvent and tetrabutylammonium difluorotriphenylsilicate (TBAT) as the additive, ligand A showed selectivity towards the formation of the branched product (18 : 1 regioselectivity) while ligand B provided more of the linear product (3.6 : 1 regioselectivity) selectively over other. Steric factors play an important role to decide the selectivity of the product as the more bulky B shows preference towards attack on the less substituted side of the alkene. The methodology was also demonstrated to provide a convenient synthetic route for the enantioselective synthesis of Flustramine A and B (19 & 20) by simple alteration of ligands with excellent regio and stereocontrol.

2.5 Heck reactions

Steroids are polycyclic natural products exhibiting diverse biological and pharmacological activity.⁸² A large number of steroidal derivatives have been identified over the years from various sources such as animals, fungi, plants etc. and therefore there is a constant need for the development of more sophisticated and concise synthetic routes. Recently, Tietze and co-workers with the aim of developing shorter and efficient synthetic routes for accessing steroidal molecules (Estrone derivative, 21), carried out a step-wise double Heck reaction between (Z)-(2-bromoethenyl)bromobenzene and hexahydro-1H-indene derivative (Scheme 20).⁸³ One of the key features of the protocol was the highly regio- and stereoselective Heck reaction with the C–C bond formation taking place anti to the angular methyl group. This step was then followed by another ring closing intramolecular Heck reaction affording the tetracyclic product which was finally transformed into estrone derivatives 21 in good yields.

Scheme 20 Estrone (21) synthesis via regioselective double Heck reaction.

2.6 Sonogashira cross-coupling

In continuation of their studies on the preparation of 2,3,5-tri and 2,3-disubstituted furans, Bach and co-workers employed the Pd-catalysed cross-coupling methodology for accessing another naturally occurring abundant furan fatty acids 22⁸⁴ or F5 acids which are examples of 2,3,5-substituted furans (Scheme 21).⁶⁹ Palladium-catalysed regioselective Sonogashira reaction of 2,3-dibromofurfural with long chain alkyne resulted in the 2-alkynylated-3-bromofurfural as an advanced fragment for the synthesis of furan fatty acid 22 in good yields. Complete regioselectivity was observed in both the reactions for the cross-coupling reaction to take place via activation of C–Br bond in the more electrophilic 2-position rather than the less electrophilic 3-position.

Scheme 21 F5 furan fatty acid synthesis via regioselective Sonogashira reaction.

3 Conclusion and future scope (palladium-catalysed C–H activation)

The above examples demonstrate the powerful nature of the palladium-catalysed cross-coupling reactions to regioselectively couple polyhalogenated heteroaryls leading to the development of efficient protocols for the synthesis of natural products. Although a wide variety of natural products could be synthesised through the application of such methodology the cross-coupling reactions suffer from several disadvantages such as the non-ready availability of functionalised organometallic reagents or the involvement of several synthetic steps for obtaining such reagents.

In recent years a more economically attractive alternative has been presented in the form of the palladium-catalysed C–H bond activation^85,86 of heteroaryls that could overcome such problems making the synthetic sequence less cumbersome than the cross-coupling processes. For several years one of the challenges in front of the synthetic chemists was to control the regioselectivity⁸⁷ in C–H activation processes which was recently demonstrated by Ackermann and co-workers (Scheme 22) for the synthesis of the cytotoxic, naturally occurring Murrayafoline A (23).⁸⁸ The synthetic route was based on a highly regioselective one-pot modular transformation of dichloroarenes with substituted anilines via palladium-catalysed C–H activation reaction.

Scheme 22 Murrayafoline A (23) synthesis via regioselective C–H bond functionalisation.

This methodology has thus provided synthetic organic chemist with an efficient and environmentally feasible alternative for the synthesis of complex, biologically active molecules.⁸⁹ However, further works needs to be done to make this methodology commercially attractive.

Acknowledgements

This paper is dedicated to Professor Richard J. K. Taylor on the occasion of his 65^th birthday. We also would like to thank Department of Science and Technology, India for DST Inspire faculty award (IFA12-CH-22) for A.R.K.

Notes and references

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