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REVIEW
Cite this: Nat. Prod. Rep., 2014, 31, 456
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Sequential catalysis for stereoselective synthesis of complex polyketides Daniel Herkommer,† Bjo ¨ rn Schmalzbauer† and Dirk Menche*
Covering: the literature up to 2012 This review presents recent advances in sequential catalytic methods developed in our group for the rapid and stereoselective synthesis of key structural features of complex polyketides. These include a novel Received 16th September 2013
domino reaction, based on a combination of a nucleophilic addition and a Tsuji–Trost reaction, an
DOI: 10.1039/c3np70093c
innovative sequence relying on an oxidative diyne cyclization and regioselective opening, as well as sequential cross coupling strategies. The design and scope of these methods are discussed and
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applications in complex target syntheses presented.
1 2 3 3.1 3.2 3.3 4 5 5.1 5.2 6 7
Introduction Sequential catalysis Domino nucleophilic addition-Tsuij–Trost reactions Concise synthesis of tetrahydropyrans Tandem synthesis of acetal-protected 1,3-diols General concept and further applications Tandem diyne-cyclization and regioselective openings Sequential cross coupling methods Convergent macrocyclization synthesis Hetero-bis-metallated alkenes as modular reagents towards olenic systems Conclusion and perspectives References
1
Introduction
Polyketides are a structurally very diverse family of numerous natural products. They cover an exceedingly broad range of biological activities and pharmacological properties and polyketide antibiotics, antifungals, cytostatics, antiparasitics and natural insecticides are in commercial use.1 In many cases, specic molecular targets are addressed at a molecular level, which adds to their attractiveness for further advancement. As shown for the halichondrines (2, Fig. 1),2 they may be characterized by impressive structural complexities. The halichondrines (2) show extraordinary antitumor activity, both in vitro and in vivo, rendering them promising leads for the development of new anticancer agents. Further examples that have been recently investigated in our group include the highly Kekul´e-Institut f¨ ur Organische Chemie und Biochemie der Universit¨ at Bonn, Gerhard-Domagk-Str. 1, D-53121, Bonn, Germany. E-mail: [email protected] † Both authors contributed equally to this work
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potent antiproliferative agent rhizopodin (1),3 which interacts with the actin cytoskeleton,4 leupyrrin A1 (4),5 an antifungal agent as well as the antibiotic RNA polymerase inhibitor etnangien.6 From a structural point of view, polyketides are characterised by sequences of methyl as well as hydroxyl bearing stereogenic centres. Biosynthetically, they are derived by iterative condensations of acetyl and propionyl subunits and subsequent reduction of the derived b-keto-esters, generating manifold assemblies of methyl and hydroxyl-bearing stereogenic centres. Thereby, a large number of stereochemical permutations and structures with very high complexity and diversity may be formed. The chemical synthesis of complex polyketides presents an important research goal not only to enhance the oen sparse natural supply of these compounds and to support further biological applications, but also to enable structure– activity relationships (SAR) and for unambiguous stereochemical assignment. The aldol reaction mimics the biosynthetic pathway and presents one of the most important methods available for the stereocontrolled polyketide formation and a vast amount of regio-, stereo-, and enantioselective carboncarbon bond formation variants of the aldol reaction have been reported.7 However, alternative strategies to achieve these most characteristic structural assemblies have become increasingly important, including reductive couplings, crotylations, allenylations, selective radical processes, sequential substitutions, epoxide openings and rearrangements to intramolecular approaches.8 Based on these methods, great progress was achieved in the total synthesis of these structures. However, despite these oen impressive accomplishments, there remains a great demand for the development of more efficient synthetic methods to
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Review
assemble these structures in a more direct and convergent manner. Herein, we report the design, development and application of novel types of sequential processes to access key structural features of polyketides. These include an innovative domino reaction, relying on a combination of a nucleophilic addition, followed by a Tsuji–Trost reaction, as well as a tandem sequence which relies on an oxidative diyne cyclization and subsequent regioselective opening of the intermediate metallacycles. Finally, we describe a novel sequential cross coupling approach, which includes the innovative use of hetero-bismetallated alkenes as modular reagents to build up diverse side chain analogues of the polyketide etnangien in a highly convergent manner. The applicability of these methods for enabling the highly concise, as well as stereoselective synthesis of complex polyketides, has also been demonstrated.
2 Sequential catalysis A vast amount of organic transformations is known to be conducted by the use of metal complexes and they occupy a central Daniel Herkommer, born in 1984, studied chemistry at the University of Heidelberg, Germany, where he obtained his diploma in 2011 working on natural product synthesis. He performed further undergraduate studies at the University of Bristol, UK. In 2011 he started his Ph.D. thesis in Heidelberg under the supervision of Professor Dirk Menche and followed him to the University of Bonn, Germany in 2012 where he is currently working on the total synthesis of polyketide natural products. His further research interests are the synthesis of biologically active molecules.
Bj¨orn Schmalzbauer was born in 1985 in K¨ unzelsau, Germany. He studied chemistry at the Ruprecht-Karls-University of Heidelberg where he received his diploma in 2011 working on natural product total synthesis. He then joined the working group of Prof. Dirk Menche at the University of Heidelberg and moved with him to the University of Bonn in 2012 where he is currently pursuing his Ph.D. studies in the eld of total synthesis of diverse natural products with marine origin.
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position in today's preparative organic chemistry. The notion to combine several metal-mediated processes in relay-type domino sequences has gained more and more attention in recent years.9 However, despite considerable advancements in this eld, the development of efficient methods that are also applicable in complex target synthesis still remains an important research goal. Particularly desirable are domino sequences, as they combine several synthetic transformations in a one-pot process and thus enable the rapid assembly of complex architectures. To achieve high degrees of atom economy, synthetic efficiency, convergence and modularity, such methods should ideally be based on catalytic procedures. Importantly, one-pot sequential catalytic processes allow many reactions to occur in a single ask (no workup of the intermediate product, as in Scheme 1) enabling the highest degrees of synthetic and economic efficiency.
3 Domino nucleophilic additionTsuij–Trost reactions One of the most versatile and efficient methods for C–C and C–X bond formation is the palladium-catalyzed allylic substitution reaction and consequently, a broad range of procedures and applications have been reported.10 However, despite this importance, the implementation of such Tsuji–Trost type reactions in sequential processes appears not to be fully exploited, regardless of the obvious potential in enabling a rapid increase of structural complexity from simple starting materials by combining several synthetic transformations in a one-pot fashion.11 3.1
Concise synthesis of tetrahydropyrans
Substituted tetrahydropyrans (THPs) present prevalent constitutional chemotypes and underlying structural motifs in manifold natural products, registered drugs and bioactive synthons. Consequently, a plethora of strategies for the construction of such systems have been reported,12 including hetero-Diels–Alder
Dirk Menche (born 1972) studied chemistry and biochemistry at the Universities of W¨ urzburg and Caen (France). In W¨ urzburg he joined the group of Prof. G. Bringmann (Ph.D. 2002). Aer postdoctoral stays at the University of Cologne with Prof. A. Berkessel and the University of Cambridge with Prof. I. Paterson (Cambridge, U. K.), he started his independent research at the Helmholtz Centre for Infection Research in Braunschweig in 2005. Aer his habilitation with Prof. M. Kalesse, he became associate professor at the University of Heidelberg in 2008. Since 2011, he holds a chair of Organic Chemistry at the University of Bonn.
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Chosen examples of complex polyketides; the highlighted structural features correspond to the domino sequential catalytic processes described in this work.
Fig. 1
reactions, Prins cyclizations, intramolecular nucleophilic reactions, Michael reactions, cyclizations onto oxocarbenium ions and epoxides, reduction of cyclic hemi-acetals, cyclization on non-activated double bonds, or one-pot procedures based on alkene-alkyne couplings followed by ether formation. Within this research programme, we desired a more concise and direct sequence for the synthesis of THPs. Scheme 2 shows our main synthetic concept, which utilises a three-step sequential process involving an oxa-Michael addition13 and a Tsuji–Trost coupling. Along this sequence, the readily available homoallylic alcohol 5 would rstly add to a suitable acceptor-substituted alkene 6 giving enolate 7 (step 1), which would then generate a p-allyl complex 8 (step 2). Finally, this intermediate complex would be trapped by an intramolecular allylic substitution reaction, generating the desired THP motif in a highly direct fashion (step 3). Notably, this process demonstrates a high increase in structural complexity from very simple starting materials, as three new stereogenic centers are assembled along this process. Initial experiments with different Michael acceptors revealed that nitro-olens are most effective for the desired transformation. Aer evaluating various reagents (catalysts, ligands,
Scheme 1 The concept of sequential catalysis; if the second catalyst is added without isolation of the intermediate product the overall process is a domino sequential catalytic process.
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bases) and parameters (temperature, solvent) the synthetic strategy could be successfully realized, as shown in Scheme 3. Catalytic amounts of Pd2(dba)3 with PPh3, in combination with LiOtBu as a base proved to be among the most effective conditions. The phenyl- and the vinyl-substituents both reside in equatorial positions within the major products (Scheme 3), whilst the conguration of the propyl- and the nitro bearing centres differs. As shown in Scheme 3a, various further THPs were readily obtained by this domino process. Aer modication of the reaction conditions, it was also possible to apply this procedure to the synthesis of THPs bearing a tetrasubstituted carbon center (Scheme 3b). Considering the stereochemical complexity of this process, good selectivities and
Scheme 2
Three-step tandem concept for tetrahydropyran synthesis.
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Scheme 4 Mechanistic proposal via a Zimmerman–Traxler transition state to explain the observed stereochemical outcome.
3.2
Tandem synthesis of acetal-protected 1,3-diols
With this rst proof of concept, we turned our attention to consecutive 1,3-arrays of hydroxyl bearing stereogenic centres, which present the most prevalent structural phenotypes in a large variety of polyketides. In detail, we were attracted to devise a more direct route to the northern fragment of rhizopodin (Scheme 5). Inspired by the above-mentioned cascade concept, we desired to create a more direct entry to this important synthetic
Stereoselective tetrahydropyran synthesis by a domino oxa-Michael–Tsuij–Trost reaction: substrate scope (a) and generation of tetrasubstituted carbon centers (b).
Scheme 3
yields could be achieved.14,15 Importantly, the synthetic usefulness of this process is enhanced by the fact that the heterocyclic products bear two functional groups, the nitro- as well as the alkene-functionality, which may be readily further elaborated. The stereochemical outcome of this process may be rationalized by a Zimmerman–Traxler type transition-state. As shown in Scheme 4, both the C2 and C4 substituents reside in equatorial positions, in agreement with the observed stereochemical outcome towards 12. Generation of the axial conguration at C5 in turn may be explained by the chelation of the metal counterion to the ether oxygen and the nitro-group, which may be more favourable in 14, as compared to 15. Also, 14 may be more stable than 15 because of the minimization of dipole–dipole interactions with the nitronate. The substituent at C6 would then reside in a pseudo-equatorial conformation in this 6-membered chelate 14, giving the stereoisomer as observed.
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Scheme 5
Three-step tandem concept for 1,3-diol synthesis.
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synthon. Our concept involves the addition of a homoallylic alcohol 5 to a suitable carbonyl compound 18 to obtain the corresponding hemiacetal-alkoxide (step 1). The formation of the electrophilic p-allylic complex (step 2) then leads to the generation of 17 which undergoes an intramolecular allylic substitution to yield the desired 1,3-allylic alcohol 16 in a suitably protected form (step 3).16 Notably, this sequence represents one of the rst examples of hemiacetal-alkoxides as nucleophiles in allylic substitutions.10m–p,17 The realization of this concept is depicted in Scheme 6.18 The most effective conditions for the selective synthesis of syn-1,3dioxanes of type 16 relied on homoallylic alcohol 10 in acetaldehyde as a co-solvent, with a slight excess of KHMDS (1.5 eq.) and catalytic amounts of [Pd(allyl)Cl]2 (10%) and PPh3 (30%) at room temperature, in toluene. This enabled an efficient entry to protected 1,3-syn-diols 16, with good stereoselectivities and yields. The substrate scope ranged from simple phenolic or benzylic, to aliphatic compounds. The general usefulness of this novel synthetic domino sequence for polyketide synthesis was demonstrated by the convergent synthesis of the northern fragment 28 of rhizopodin (Scheme 7). The necessary chiral homoallylic alcohols are readily accessible from simple starting materials, e.g. via the regioselective opening of terminal epoxides (21 to 24), or by the asymmetric allylation of aldehydes (22 to 24) with subsequent cross metathesis (viz 24 and 25 to 26). The pivotal reaction proceeded with high yield and selectivity, demonstrating the usefulness
Review
Scheme 7
and applicability of our approach. Importantly, the generated terminal alkene functionality may serve as a synthetic handle for the further elaboration of the target, as demonstrated in a fragment synthesis of macrolide RK-397 (not shown).18 3.3
Scheme 6 Concise synthesis of acetal-protected 1,3-syn-diols by a tandem hemiacetal/Tsuji–Trost reaction.
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Concise synthesis of the northern fragment 28 of
rhizopodin.
General concept and further applications
Based on these conformations of our novel type of domino sequence, a general concept for this tandem relay, relying on a nucleophilic substitution and Tsuji–Trost reaction, may be proposed. As shown in Scheme 8, it includes the coupling of different homoallylic nucleophiles, with X being oxygen, nitrogen or sulphur, to different types of electrophiles. These may be Michael acceptors 6 (le part), hetero-olens 34, e.g. imines or carbonyls (middle part) or allene homologues 37, e.g. cyanates or thiocyanates (right part) to give the corresponding 6-membered heterocycles 9, 36 or 38, respectively, with X being oxygen, nitrogen, sulphur or carbon. In all cases, these reactions should proceed by an anionic relay. For further proof, we turned our attention to 1,3-diamines and 1,3-aminoalcohols as prevalent structural motives in various bioactive natural products and medical compounds.19 In an effort to further evaluate the generality of our tandem combination of nucleophilic substitution and Tsuji–Trost reaction, we were particularly attracted to develop a more general approach to these compounds.20 Scheme 9 shows the implementation of this concept for the efficient synthesis of 1,3-syn and -anti tetrahydropyrimidinones (syn- and anti-42). Importantly, a modular and stereodivergent cyclization of urea-type substrates 41, by means of an intramolecular allylic substitution, was realized.21 This reaction proceeds with excellent yields (up to 99%) and stereoselectivities (>20 : 1). Notably, both the syn- and the anti-diastereomers can be obtained, with excellent asymmetric induction in a divergent manner from the same substrate, solely
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Scheme 8
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General domino concept based on a nucleophilic addition and Tsuji–Trost coupling.
Tandem processes for the stereoselective synthesis of 1,3-amino-alcohols.
Scheme 10
Scheme 9 Tandem processes for the stereoselective synthesis of synand anti-1,3-diamines.
controlled by solvent effects. The products of this pivotal conversion could be easily transformed to the corresponding free syn- and anti-amines 43. The general scope of our approach was then further conrmed in the synthesis of 1,3-syn oxazines 46 by a three step, sequential process of a hemi-aminalisation22, followed by a
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Tsuji–Trost reaction (Scheme 10).23 With this process, up to two new stereogenic centres can be generated, in a convergent and concise manner. Again, the starting materials are easily accessible and the product oxazines 46 may be transformed to the 1,3-aminoalcohols 47.
4 Tandem diyne-cyclization and regioselective openings The leupyrrins (4)5 are structurally unique myxobacterial metabolites, which exhibit potent biological activities against various fungi and eukaryotic cells. A key structural feature of these potent bioactive agents includes an unsymmetrically
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substituted tetrahydrofuran core, with two exocyclic, E-congured double bonds, that remains without precedence and therefore, no synthetic strategy has been developed. Following a highly advantageous synthetic approach, this structural feature was envisioned to be derived by a three step sequence based on an oxidative diyne cyclization. In the past decades oxidative diyne cyclizations using lowvalent zirconocene and titanocene species, of type ‘Cp2M(II)’ have reached a prominent position for alkyne functionalization.24 Mechanistically, the reaction proceeds via intermediate metalla-cyclopentadienes 49, which can be cleaved with various reagents (Scheme 11). While symmetric cleavages by complete hydrolysis or dihalogenation are well established,25 a regioselective, stepwise opening through 50 has been much less advanced. A rst promising result, from the group of Takahashi in 1998, reported a selective monohalogenation of a zirconacyclopentadiene, bearing a mixed aliphatic-aromatic substitution pattern,26 based on the distinguishable basicity of both a-carbon atoms. Within our study programme the rst example for a regioselective opening of metallacycles with sterically similar demanding aliphatic side chains was realized. Importantly, this relies on an innovative use of remote directing groups. Such a sequence would allow a highly concise entry to the tetrahydrofuran core. Based on this synthetic design, a three-step, one-pot tandem process, including a zirconocene mediated cyclization of
unsymmetric aliphatic 1,6-diynes with a subsequent monohalogenation, was developed and mechanistically investigated.27 As shown in Scheme 12, this sequence includes a highly regioselective opening of zirconacyclopentadienes, of type 49, with NBS, which are derived by a cyclization from 1,6-diyne 52. This sequence enables a specic entry into monobrominated products 54 or 55. Notably, the selectivity prole may be inverted, i.e. the formation of 54 or 55, depending on the protective groups. This powerful proof of our concept of the critical inuence of a remote directing group was conrmed by DFT calculations, using Gaussian09 at the B3LYP level, revealing a pronounced tendency of the side chain functionality to interact with the metal (Scheme 12). The optimized geometries suggest that a stabilization may be caused by a diminished distance of the OMe group or the OPMB group to the metal center. Consequently, the Cp-rings are pushed closer to C15 or C18, which then leads to selective brominations. Importantly, this novel domino sequence was then applicable to an efficient synthesis of the authentic tetrahydrofuran core of the leupyrrins. Accordingly, the transformation of 58, which already bears all the necessary functionalities of the target molecule at C13, C14 and C21 in a suitable protected
Scheme 11 Regioselective opening of zirconacyclopentadienes: proposed one-pot synthesis of the furan core of the leupyrrins.
Scheme 12
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Tandem zirconocene-mediated diyne-cyclization and regioselective opening of zirconacyclopentadienes.
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form, was investigated. Importantly, this compound is easily accessible through etherication of 56 with 57 (Scheme 13). The adjacent zirconocene mediated, one pot cyclization regioselective opening of 59 again proceeded with high yields and selectivities, demonstrating the generality of our approach. Eventually, the required methyl group was installed by lithiation of 60 by means of tBuLi, followed by trapping of this lithiated species with Me2SO4, to give the desired C18 methylsubstituted diene 61 in a 53% yield, demonstrating the true
applicability of this sequential process in complex target synthesis.28
5 Sequential cross coupling methods 5.1
Convergent macrocyclization synthesis
Palladium-catalysed cross couplings are among the most important methods for C–C bond formation. Most prominently, the Suzuki and Stille coupling are omnipresent in complex target syntheses. In contrast, slightly fewer applications of Heck reactions in complex target synthesis have been reported, despite the obvious advantage of using a non-functionalized alkene and more specically, only a few examples of
Potent polyene macrolides etnangien and etnangien methyl ester and bis-metallated alkene synthons 70 and 71.
Fig. 2 Scheme 13 Concise synthesis of the furan core of the leupyrrins.
Scheme 14
Chemoselective cross-coupling strategy to the macrocyclic core of rhizopodin.
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intramolecular Heck reactions in the total synthesis of complex natural products have been applied.29 In an effort to further expand the scope of Heck reactions and to effectively use the unique advantage, as compared to the more conventional cross coupling reactions, we envisioned a sequential process relying on a Suzuki and Heck reaction for a highly concise synthesis of the macrocyclic core of rhizopodin (1),30 a potent G-actin polymerization inhibitor31 obtained from the myxobacterium Myxococcus stipitatus (Fig. 1).32 In detail, we envisioned a highly convergent approach with a sequential chemoselective crosscoupling strategy as a key step, exploiting the orthogonal reactivity of a dual functionalised precursor by sequential application of a Suzuki coupling and a Heck macrocyclization.33
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For the synthesis of the macrocyclic core, rstly acid 62 was esteried with the sterically hindered secondary alcohol of fragment 63, using Yamaguchi's reagent. The building block 64 bears both a terminal olen and a vinyliodine moiety, to enable the desired chemoselective cross coupling strategy (Scheme 14). As the rst step of our sequence, an intermolecular Suzuki coupling with boronate 65 proceeded smoothly at the vinyliodine terminus and afforded solely the desired E-isomer. Aer Yamaguchi esterication with acid 62, the terminal non-funtionalized alkene of 66 was then coupled to the terminal vinyliodide, in a Heck reaction. This cyclization required some optimisation in regards of the catalyst, additives and solvent and was found to proceed most effectively with Pd(OAc)2, K2CO3 and NBu4Cl in DMF, to give the macrocyclic core 67 in 77% yield and an E/Z-ratio of 5 : 1. In conclusion, the macrocyclic core 67 was prepared in only four steps from the elaborate building blocks 62, 63 and 65, with an overall yield of 64%, using a highly chemoselective crosscoupling strategy. Notably, this is one of the most advanced applications of intramolecular Heck reactions, demonstrating its power in complex natural product synthesis.29c,d,34 5.2 Hetero-bis-metallated alkenes as modular reagents towards olenic systems
General sequence for the synthesis of hetero-bis-metallated reagents 70 and 71.
Scheme 15
A key structural feature of the potent polyketide antibiotic etnangien29c,d,35 and polyketides in general are extended polyene fragments. For a convergent synthesis of such types of synthons,
Scheme 16 Modular, three-fragment coupling synthesis of the side chain analogues of etnangien based on hetero-bis-metallated alkenes.
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we envisioned the application and further development of hetero-bis-metallated alkenes, with conjugated and isolated olen subunits, which could be used in a sequential crosscoupling process (Fig. 2).36 As shown in Scheme 15, we were able to devise a practicable and general methodology for the synthesis of such type of reagents, bearing conjugated and isolated olen subunits, based on a straightforward three-step sequence, involving a hydrostannylation of alkynols 72,37 subsequent oxidation of the derived primary alcohols and a Boryl–Takai olenation38 of the aldehydes (Scheme 15). Demonstrating the utility of these reagents,39 we then constructed different polyene side chains of the polyketide etnangien in a highly concise and modular fashion (Scheme 16) via a convergent Stille/Suzuki–Miyaura cross-coupling sequence, being either fully or only partly conjugated. Notably, this enables a modular access also to more stable analogues, which may be important to devise a more stable analogue of these highly potent, but labile polyene antibiotics. It is expected that these novel bifunctional reagents will become effective building blocks for convergent polyene synthesis and analogues in modular and divergent approaches.
6
Conclusion and perspectives
In this review, we presented innovative strategies for the highly concise synthesis of key structural elements of polyketides. In detail, a novel domino concept based on a combination of a nucleophilic addition reaction and a Tsuji–Trost coupling has been devised and developed, which allows a highly concise entry into most diverse building blocks, including tetrahydropyrans, 1,3-amino alcohols, -diamines or -diols. Importantly, these methods proceed with high stereoselectivity and high degrees of asymmetric induction, purely based on substrate control, adding to the general usefulness of these procedures. Furthermore, a novel sequential process involving a zirconocene-mediated diyne-cyclization and highly regioselective opening of the intermediate metalcyclopentadienes has been developed as an efficient entry into complex target synthesis. Importantly, these two sequential processes combine several synthetic transformations in a one-pot process and thus, enable the rapid assembly of structural complexity. Additionally, an elegant method for the rapid assembly of an elaborate macrocycle was presented, using a chemoselective cross-coupling strategy as key step, exploiting the orthogonal reactivity of a dual functionalised precursor by sequential application of a Suzuki coupling and a Heck macrocyclization. Finally, heterobis-metallated alkenes were presented as modular reagents towards the synthesis of conjugated and isolated olenic systems, enabling a rapid access to side chain analogues of etnangien, in a highly concise and convergent manner. The true applicability of all these methods in complex target synthesis has been demonstrated and enabled a much more concise entry into the potent myxobacterial macrolides rhizopodin, etnangien and leupyrrin. It is expected that these novel sequences will be further explored and applied and speed up the process of complex polyketide synthesis. We anticipate that these methods
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will be further developed and applied in the synthesis of diverse polyketides and structurally related complex targets, which will be crucial for the advancement of these promising bioactive agents.
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References
1 (a) C. Hertweck, Angew. Chem., Int. Ed., 2009, 48, 4688; (b) D. Menche, Nat. Prod. Rep., 2008, 25, 905; (c) K. J. Weissman and R. M¨ uller, Nat. Prod. Rep., 2010, 27, 1276; (d) M. Kretschmer and D. Menche, Synlett, 2010, 2989. 2 For a leading reference, see: K. Namba, H.-S. Jun and Y. Kishi, J. Am. Chem. Soc., 2004, 126, 7770. 3 For a leading reference, see: M. Dieckmann, M. Kretschmer, P. Li, S. Rudolph, D. Herkommer and D. Menche, Angew. Chem., Int. Ed., 2012, 51, 5667. 4 T. M. A. Gronewold, F. Sasse, H. L¨ unsdorf and H. Reichenbach, Cell Tissue Res., 1999, 295, 121. 5 (a) H. B. Bode, H. Irschik, S. C. Wenzel, H. Reichenbach, R. M¨ uller and G. H¨ oe, J. Nat. Prod., 2003, 66, 1203; (b) H. B. Bode, S. C. Wenzel, H. Irschik, G. H¨ oe and R. M¨ uller, Angew. Chem., Int. Ed., 2004, 43, 4163; (c) M. Kopp, H. Irschik, K. Gemperlein, K. Buntin, P. Meiser, K. J. Weissman, H. B. Bode and R. M¨ uller, Mol. BioSyst., 2011, 7, 1549. 6 (a) G. H¨ oe, H. Reichenbach, H. Irschik, D. Schummer, German Patent DE 196 30 980 A1: 1–7 (5.2. 1998); (b) H. Irschik, D. Schummer, G. H¨ oe, H. Reichenbach, H. Steinmetz and R. Jansen, J. Nat. Prod., 2007, 70, 1060; (c) D. Menche, F. Arikan, O. Perlova, N. Horstmann, W. Ahlbrecht, S. Wenzel, R. Jansen, H. Irschik and R. M¨ uller, J. Am. Chem. Soc., 2008, 130, 14234. 7 (a) B. M. Trost and C. S. Brindle, Chem. Soc. Rev., 2010, 39, 1600; (b) X. Ariza, J. Garcia, P. Romea and F. Urp´ı, Synthesis, 2011, 2175; (c) B. Schetter and R. Mahrwald, Angew. Chem., Int. Ed., 2006, 45, 7506; (d) Modern Methods in Stereoselective Aldol Reactions, ed. R. Mahrwald, WileyVCH, Weinheim, 2013. 8 J. Li and D. Menche, Synthesis, 2009, 2293. 9 For reviews on tandem reactions by several metal mediated processes, see: (a) J.-C. Wasilke, S. J. Obrey, R. T. Baker and G. C. Bazan, Chem. Rev., 2005, 105, 1001; (b) I. Ryu and N. Sonoda, Chem. Rev., 1996, 96, 177; (c) P. J. Parsons, C. S. Penkett and A. J. Shell, Chem. Rev., 1996, 96, 195; (d) L. F. Tietze, G. Brasche and K. M. Gericke, Domino Reactions in Organic Synthesis, 2006, Wiley-VCH, Weinheim; (e) S. Inuki, A. Iwata, S. Oishi, N. Fujii and H. J. Ohno, J. Org. Chem., 2011, 76, 2072; (f) S. Newman, J. Howell, N. Nicolaus and M. J. Lautens, J. Am. Chem. Soc., 2011, 133, 14916; (g) T. Vlaar, E. Ruijter and R. Orru, Adv. Synth.Catal., 2011, 353, 809; (h) T. Piou, L. Neuville and J. Zhu, Org. Lett., 2012, 14, 3760. 10 For general reviews, see: (a) B. M. Trost and C. Lee, Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley-VCH, New York, 2nd edn, 2000, p. 593; (b) A. Pfaltz and M. Lautens, Comprehensive Asymmetric Catalysis I–III, ed. E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Springer, Berlin, 1999, p. 833; (c)
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B. M. Trost and M. Crawley, Chem. Rev., 2003, 103, 2921; (d) S. F¨ orster, G. Helmchen and U. Kazmaier, Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley, Hoboken, 3rd edn, 2010, p. 49; for addition of O-nucleophiles to p-allyl intermediates, see: ; (e) C. Morin and L. Ogier, Carbohydr. Res., 1998, 310, 277; (f) D. J. Covell and M. C. White, Angew. Chem., Int. Ed., 2008, 47, 6448; (g) J. S. Cannon, S. F. Kirsch and L. E. Overman, J. Am. Chem. Soc., 2010, 132, 15185; (h) A. N. Campbell, P. B. White, I. A. Guzei and S. S. Stahl, J. Am. Chem. Soc., 2010, 132, 15116; (i) A. D. Cuiper, R. M. Kellogg and B. L. Feringa, Chem. Commun., 1998, 655; (j) H. van der Deen, A. van Oeveren, R. M. Kellogg and B. L. Feringa, Tetrahedron Lett., 1999, 40, 1755; (k) H. Nakano, J. Yokoyama, R. Fujita and H. Hongo, Tetrahedron Lett., 2002, 43, 7761; (l) A. R. Haight, E. J. Stoner, M. J. Peterson and V. K. Grover, J. Org. Chem., 2003, 68, 8092; (m) R. Lakhmiri, P. Lhoste, B. Kryczka and D. Sinou, J. Carbohydr. Chem., 1993, 12, 223; (n) I. Frappa, B. Kryczka, P. Lhoste, S. Porwanskia and D. Sinou, J. Carbohydr. Chem., 1997, 16, 891; (o) I. Frappa, B. Kryczka, P. Lhoste, S. Porwanskia, D. Sinou and A. Zawisza, J. Carbohydr. Chem., 1998, 17, 1117; for a diastereoselective synthesis of acetal-protected syn 1,3-diols by a basecatalyzed intramolecular conjugate addition of hemiacetalderived alkoxide nucleophiles, see: ; (p) D. A. Evans and J. A. Gauchet-Prunet, J. Org. Chem., 1993, 58, 2446. (a) B. M. Trost, S. M. Silverman and J. P. Stambuli, J. Am. Chem. Soc., 2007, 129, 12398; (b) R. Shintani, S. Park, W.-L. Duan and T. Hayashi, Angew. Chem., Int. Ed., 2007, 46, 5901; (c) R. Shintani, M. Murakami, T. Tsuji, H. Tanno and T. Hayashi, Org. Lett., 2009, 11, 5642; (d) F. J. Williams and E. R. Jarvo, Angew. Chem., Int. Ed., 2011, 50, 4459. For reviews, see: (a) P. A. Clarke and S. Santos, Eur. J. Org. Chem., 2006, 2045; (b) H. Fuwa, Heterocycles, 2012, 85, 1255. (a) C. F. Nising and S. Br¨ ase, Chem. Soc. Rev., 2008, 37, 1218; (b) C. F. Nising and S. Br¨ ase, Chem. Soc. Rev., 2012, 41, 988. L. Wang, P. Li and D. Menche, Angew. Chem., Int. Ed., 2010, 49, 9270. L. Wang and D. Menche, J. Org. Chem., 2012, 77, 10811. A related strategy has been reported by the group of Cossy using cyclic borates. However, in this study the 1,3-diols were obtained with only poor diastereoselectivities: J. Cluzeau, J. Capdevieille and J. Cossy, Tetrahedron Lett., 2005, 46, 6945. For an alternative domino sequence for 1,3-anti diol synthesis, see: M. Dieckmann and D. Menche, Org. Lett., 2013, 15, 228. L. Wang and D. Menche, Angew. Chem., Int. Ed., 2012, 51, 9425. For the synthesis of amino alcoholes see: (a) F. Koehler, H. J. Gais and G. Raabe, Org. Lett., 2007, 9, 1231; (b) D. N. Zalatan and J. Du Bois, J. Am. Chem. Soc., 2008, 130, 9220; (c) B. Weiner, A. Baeza, T. Jerphagnon and B. L. Feringa, J. Am. Chem. Soc., 2009, 131, 9473; (d) G. T. Rice and M. C. White, J. Am. Chem. Soc., 2009, 131, 11707; (e) S. M. Paradine and M. C. White, J. Am. Chem. Soc., 2012, 134, 2036; (f) R. A. T. M. van Benthem,
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20
21 22
23 24
25
26 27 28 29
30
H. Hiemstra, J. J. Michels and W. N. Speckamp, J. Chem. Soc., Chem. Commun., 1994, 357. For a recent review on chiral amine synthesis, see: T. C. Nugent and M. El-Shazly, Adv. Synth. Catal., 2010, 352, 753. For previous work from our group on direct stereoselective amine synthesis, see: (a) D. Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter and S. Rudolph, Org. Lett., 2006, 8, 741; (b) D. Menche, F. Arikan, J. Li and S. Rudolph, Org. Lett., 2007, 9, 267. M. Morgen, S. Bretzke, P. Li and D. Menche, Org. Lett., 2010, 12, 4494. For a domino reaction involving a hemiaminalization, see: T. Urushima, D. Sakamoto, H. Ishikawa and Y. Hayashi, Org. Lett., 2010, 12, 4588. B. Tang, L. Wang and D. Menche, Synlett, 2013, 24, 625. For Ti-mediated examples, see: (a) W. A. Nugent and J. C. Calabrese, J. Am. Chem. Soc., 1984, 106, 6422; (b) W. A. Nugent, D. L. Thorn and R. L. Harlow, J. Am. Chem. Soc., 1987, 109, 2788. For Zr-mediated examples, see: ; (c) E. Negishi, F. E. Cederbaum and T. Takahashi, Tetrahedron Lett., 1986, 27, 2829; (d) E. Negishi, S. J. Holmes, J. M. Tour, J. A. Miller, F. E. Cederbaum, D. R. Swanson and T. Takahashi, J. Am. Chem. Soc., 1989, 111, 3336; (e) M. I. Kemp, S. J. Coote and R. J. Whitby, Synthesis, 1998, (Sup. 1), 557; (f) R. T. Chen and K. T. Wong, Tetrahedron Lett., 2002, 43, 3313. (a) S. L. Buchwald and R. B. Nielsen, Chem. Rev., 1988, 88, 1047; (b) S. L. Buchwald and R. B. Nielsen, J. Am. Chem. Soc., 1989, 111, 2870. H. Ubayama, Z. Xi and T. Takahashi, Chem. Lett., 1998, 27, 517. T. Debnar, S. Dreisigacker and D. Menche, Chem. Commun., 2013, 49, 725. T. Debnar, T. Wang and D. Menche, Org. Lett., 2013, 15, 2774. (a) A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945; (b) M. Christmann, U. Bhatt, M. Quitschalle, E. Claus and M. Kalesse, Angew. Chem., Int. Ed., 2000, 39, 4364; (c) P. Li, J. Li, F. Arikan, W. Ahlbrecht, M. Dieckmann and D. Menche, J. Am. Chem. Soc., 2009, 131, 11678; (d) P. Li, J. Li, F. Arikan, W. Ahlbrecht, M. Dieckmann and D. Menche, J. Org. Chem., 2010, 75, 2429. For fragment syntheses see: (a) Z. Cheng, L. Song, Z. Xu and T. Ye, Org. Lett., 2010, 12, 2036; (b) T. Chakraborty, K. K. Pulukuri and M. Sreekanth, Tetrahedron Lett., 2010, 51, 6444; (c) T. K. Chakraborty, M. Sreekanth and K. K. Pulukuri, Tetrahedron Lett., 2011, 52, 59; (d) K. K. Pulukuri and T. K. Chakraborty, Org. Lett., 2012, 14, 2858; (e) M. Kretschmer and D. Menche, Org. Lett., 2012, 14, 382. For synthesis of the originally proposed monomeric structure see: K. C. Nicolaou, X. Jiang, P. J. Lindsay-Scott, A. Corbu, S. Yamashiro, A. Bacconi and V. M. Fowler, Angew. Chem., Int. Ed., 2011, 50, 1139. For total syntheses see: ; (f) M. Dieckmann, M. Kretschmer, P. Li, S. Rudolph, D. Herkommer and D. Menche, Angew. Chem., Int. Ed., 2012, 51, 5667; (g) S. M. Dalby, J. Goodwin-Tindall and Paterson, Angew. Chem., Int. Ed.,
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32
33 34
2013, 52, 6517; (h) M. Kretschmer, M. Dieckmann, P. Li, S. Rudolph, D. Herkommer, J. Troendlin and D. Menche, Chem.–Eur. J., 2013, 19, 15993. For reviews on actin-binding macrolides, see: (a) K.-S. Yeung and I. Paterson, Angew. Chem., Int. Ed., 2002, 41, 4632; (b) J. S. Allingham, V. A. Klenchin and I. Rayment, Cell. Mol. Life Sci., 2006, 63, 2119. (a) R. Jansen, H. Steinmetz, F. Sasse, W.-D. Schubert, G. Hagel¨ uken, S. C. Albrecht and R. M¨ uller, Tetrahedron Lett., 2008, 49, 5796; (b) N. Horstmann and D. Menche, Chem. Commun., 2008, 5173; (c) G. Hagel¨ uken, G. Albrecht, R. Jansen, H. Steinmetz, D. Heinz, M. Kalesse, F. Sasse and W.-D. Schubert, Angew. Chem., Int. Ed., 2009, 48, 595. M. Dieckmann, S. Rudolph, S. Dreisigacker and D. Menche, J. Org. Chem., 2012, 77, 10782. (a) D. Menche, J. Hassfeld, J. Li and S. Rudolph, J. Am. Chem. Soc., 2007, 129, 6100; (b) D. Menche, J. Hassfeld, J. Li, K. Mayer and S. Rudolph, J. Org. Chem., 2009, 74, 7220.
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35 D. Menche, P. Li and H. Irschik, Bioorg. Med. Chem. Lett., 2010, 20, 939. 36 (a) R. S. Coleman and M. C. Walczak, Org. Lett., 2005, 7, 2289; (b) R. S. Coleman, X. Lu and I. Modolo, J. Am. Chem. Soc., 2007, 129, 3826; (c) F. Lhermitte and B. Carboni, Synlett, 1996, 377; (d) R. S. Coleman, M. C. Walczak and E. L. Campbell, J. Am. Chem. Soc., 2005, 127, 16038; (e) R. S. Coleman and M. C. Walczak, J. Org. Chem., 2006, 71, 9841; (f) R. S. Coleman and X. Lu, Chem. Commun., 2006, 423. 37 A. Darwish, A. Lang, T. Kim and J. M. Chong, Org. Lett., 2008, 10, 861. 38 K. Takai, N. Shinomiya, H. Kaihara, N. Yoshida and T. Moriwake, Synlett, 1995, 963. 39 (a) M. Altendorfer and D. Menche, Chem. Commun., 2012, 48, 8267; (b) M. Altendorfer, A. Raja, F. Sasse, H. Irschik and D. Menche, Org. Biomol. Chem., 2013, 11, 2116; (c) M. Altendorfer, H. Irschik and D. Menche, Bioorg. Med. Chem. Lett., 2012, 22, 5731.
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REVIEW
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Sequential catalysis for stereoselective synthesis of complex polyketides Daniel Herkommer,† Bjo ¨ rn Schmalzbauer† and Dirk Menche*
Covering: the literature up to 2012 This review presents recent advances in sequential catalytic methods developed in our group for the rapid and stereoselective synthesis of key structural features of complex polyketides. These include a novel Received 16th September 2013
domino reaction, based on a combination of a nucleophilic addition and a Tsuji–Trost reaction, an
DOI: 10.1039/c3np70093c
innovative sequence relying on an oxidative diyne cyclization and regioselective opening, as well as sequential cross coupling strategies. The design and scope of these methods are discussed and
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applications in complex target syntheses presented.
1 2 3 3.1 3.2 3.3 4 5 5.1 5.2 6 7
Introduction Sequential catalysis Domino nucleophilic addition-Tsuij–Trost reactions Concise synthesis of tetrahydropyrans Tandem synthesis of acetal-protected 1,3-diols General concept and further applications Tandem diyne-cyclization and regioselective openings Sequential cross coupling methods Convergent macrocyclization synthesis Hetero-bis-metallated alkenes as modular reagents towards olenic systems Conclusion and perspectives References
1
Introduction
Polyketides are a structurally very diverse family of numerous natural products. They cover an exceedingly broad range of biological activities and pharmacological properties and polyketide antibiotics, antifungals, cytostatics, antiparasitics and natural insecticides are in commercial use.1 In many cases, specic molecular targets are addressed at a molecular level, which adds to their attractiveness for further advancement. As shown for the halichondrines (2, Fig. 1),2 they may be characterized by impressive structural complexities. The halichondrines (2) show extraordinary antitumor activity, both in vitro and in vivo, rendering them promising leads for the development of new anticancer agents. Further examples that have been recently investigated in our group include the highly Kekul´e-Institut f¨ ur Organische Chemie und Biochemie der Universit¨ at Bonn, Gerhard-Domagk-Str. 1, D-53121, Bonn, Germany. E-mail: [email protected] † Both authors contributed equally to this work
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potent antiproliferative agent rhizopodin (1),3 which interacts with the actin cytoskeleton,4 leupyrrin A1 (4),5 an antifungal agent as well as the antibiotic RNA polymerase inhibitor etnangien.6 From a structural point of view, polyketides are characterised by sequences of methyl as well as hydroxyl bearing stereogenic centres. Biosynthetically, they are derived by iterative condensations of acetyl and propionyl subunits and subsequent reduction of the derived b-keto-esters, generating manifold assemblies of methyl and hydroxyl-bearing stereogenic centres. Thereby, a large number of stereochemical permutations and structures with very high complexity and diversity may be formed. The chemical synthesis of complex polyketides presents an important research goal not only to enhance the oen sparse natural supply of these compounds and to support further biological applications, but also to enable structure– activity relationships (SAR) and for unambiguous stereochemical assignment. The aldol reaction mimics the biosynthetic pathway and presents one of the most important methods available for the stereocontrolled polyketide formation and a vast amount of regio-, stereo-, and enantioselective carboncarbon bond formation variants of the aldol reaction have been reported.7 However, alternative strategies to achieve these most characteristic structural assemblies have become increasingly important, including reductive couplings, crotylations, allenylations, selective radical processes, sequential substitutions, epoxide openings and rearrangements to intramolecular approaches.8 Based on these methods, great progress was achieved in the total synthesis of these structures. However, despite these oen impressive accomplishments, there remains a great demand for the development of more efficient synthetic methods to
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assemble these structures in a more direct and convergent manner. Herein, we report the design, development and application of novel types of sequential processes to access key structural features of polyketides. These include an innovative domino reaction, relying on a combination of a nucleophilic addition, followed by a Tsuji–Trost reaction, as well as a tandem sequence which relies on an oxidative diyne cyclization and subsequent regioselective opening of the intermediate metallacycles. Finally, we describe a novel sequential cross coupling approach, which includes the innovative use of hetero-bismetallated alkenes as modular reagents to build up diverse side chain analogues of the polyketide etnangien in a highly convergent manner. The applicability of these methods for enabling the highly concise, as well as stereoselective synthesis of complex polyketides, has also been demonstrated.
2 Sequential catalysis A vast amount of organic transformations is known to be conducted by the use of metal complexes and they occupy a central Daniel Herkommer, born in 1984, studied chemistry at the University of Heidelberg, Germany, where he obtained his diploma in 2011 working on natural product synthesis. He performed further undergraduate studies at the University of Bristol, UK. In 2011 he started his Ph.D. thesis in Heidelberg under the supervision of Professor Dirk Menche and followed him to the University of Bonn, Germany in 2012 where he is currently working on the total synthesis of polyketide natural products. His further research interests are the synthesis of biologically active molecules.
Bj¨orn Schmalzbauer was born in 1985 in K¨ unzelsau, Germany. He studied chemistry at the Ruprecht-Karls-University of Heidelberg where he received his diploma in 2011 working on natural product total synthesis. He then joined the working group of Prof. Dirk Menche at the University of Heidelberg and moved with him to the University of Bonn in 2012 where he is currently pursuing his Ph.D. studies in the eld of total synthesis of diverse natural products with marine origin.
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position in today's preparative organic chemistry. The notion to combine several metal-mediated processes in relay-type domino sequences has gained more and more attention in recent years.9 However, despite considerable advancements in this eld, the development of efficient methods that are also applicable in complex target synthesis still remains an important research goal. Particularly desirable are domino sequences, as they combine several synthetic transformations in a one-pot process and thus enable the rapid assembly of complex architectures. To achieve high degrees of atom economy, synthetic efficiency, convergence and modularity, such methods should ideally be based on catalytic procedures. Importantly, one-pot sequential catalytic processes allow many reactions to occur in a single ask (no workup of the intermediate product, as in Scheme 1) enabling the highest degrees of synthetic and economic efficiency.
3 Domino nucleophilic additionTsuij–Trost reactions One of the most versatile and efficient methods for C–C and C–X bond formation is the palladium-catalyzed allylic substitution reaction and consequently, a broad range of procedures and applications have been reported.10 However, despite this importance, the implementation of such Tsuji–Trost type reactions in sequential processes appears not to be fully exploited, regardless of the obvious potential in enabling a rapid increase of structural complexity from simple starting materials by combining several synthetic transformations in a one-pot fashion.11 3.1
Concise synthesis of tetrahydropyrans
Substituted tetrahydropyrans (THPs) present prevalent constitutional chemotypes and underlying structural motifs in manifold natural products, registered drugs and bioactive synthons. Consequently, a plethora of strategies for the construction of such systems have been reported,12 including hetero-Diels–Alder
Dirk Menche (born 1972) studied chemistry and biochemistry at the Universities of W¨ urzburg and Caen (France). In W¨ urzburg he joined the group of Prof. G. Bringmann (Ph.D. 2002). Aer postdoctoral stays at the University of Cologne with Prof. A. Berkessel and the University of Cambridge with Prof. I. Paterson (Cambridge, U. K.), he started his independent research at the Helmholtz Centre for Infection Research in Braunschweig in 2005. Aer his habilitation with Prof. M. Kalesse, he became associate professor at the University of Heidelberg in 2008. Since 2011, he holds a chair of Organic Chemistry at the University of Bonn.
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Chosen examples of complex polyketides; the highlighted structural features correspond to the domino sequential catalytic processes described in this work.
Fig. 1
reactions, Prins cyclizations, intramolecular nucleophilic reactions, Michael reactions, cyclizations onto oxocarbenium ions and epoxides, reduction of cyclic hemi-acetals, cyclization on non-activated double bonds, or one-pot procedures based on alkene-alkyne couplings followed by ether formation. Within this research programme, we desired a more concise and direct sequence for the synthesis of THPs. Scheme 2 shows our main synthetic concept, which utilises a three-step sequential process involving an oxa-Michael addition13 and a Tsuji–Trost coupling. Along this sequence, the readily available homoallylic alcohol 5 would rstly add to a suitable acceptor-substituted alkene 6 giving enolate 7 (step 1), which would then generate a p-allyl complex 8 (step 2). Finally, this intermediate complex would be trapped by an intramolecular allylic substitution reaction, generating the desired THP motif in a highly direct fashion (step 3). Notably, this process demonstrates a high increase in structural complexity from very simple starting materials, as three new stereogenic centers are assembled along this process. Initial experiments with different Michael acceptors revealed that nitro-olens are most effective for the desired transformation. Aer evaluating various reagents (catalysts, ligands,
Scheme 1 The concept of sequential catalysis; if the second catalyst is added without isolation of the intermediate product the overall process is a domino sequential catalytic process.
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bases) and parameters (temperature, solvent) the synthetic strategy could be successfully realized, as shown in Scheme 3. Catalytic amounts of Pd2(dba)3 with PPh3, in combination with LiOtBu as a base proved to be among the most effective conditions. The phenyl- and the vinyl-substituents both reside in equatorial positions within the major products (Scheme 3), whilst the conguration of the propyl- and the nitro bearing centres differs. As shown in Scheme 3a, various further THPs were readily obtained by this domino process. Aer modication of the reaction conditions, it was also possible to apply this procedure to the synthesis of THPs bearing a tetrasubstituted carbon center (Scheme 3b). Considering the stereochemical complexity of this process, good selectivities and
Scheme 2
Three-step tandem concept for tetrahydropyran synthesis.
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Scheme 4 Mechanistic proposal via a Zimmerman–Traxler transition state to explain the observed stereochemical outcome.
3.2
Tandem synthesis of acetal-protected 1,3-diols
With this rst proof of concept, we turned our attention to consecutive 1,3-arrays of hydroxyl bearing stereogenic centres, which present the most prevalent structural phenotypes in a large variety of polyketides. In detail, we were attracted to devise a more direct route to the northern fragment of rhizopodin (Scheme 5). Inspired by the above-mentioned cascade concept, we desired to create a more direct entry to this important synthetic
Stereoselective tetrahydropyran synthesis by a domino oxa-Michael–Tsuij–Trost reaction: substrate scope (a) and generation of tetrasubstituted carbon centers (b).
Scheme 3
yields could be achieved.14,15 Importantly, the synthetic usefulness of this process is enhanced by the fact that the heterocyclic products bear two functional groups, the nitro- as well as the alkene-functionality, which may be readily further elaborated. The stereochemical outcome of this process may be rationalized by a Zimmerman–Traxler type transition-state. As shown in Scheme 4, both the C2 and C4 substituents reside in equatorial positions, in agreement with the observed stereochemical outcome towards 12. Generation of the axial conguration at C5 in turn may be explained by the chelation of the metal counterion to the ether oxygen and the nitro-group, which may be more favourable in 14, as compared to 15. Also, 14 may be more stable than 15 because of the minimization of dipole–dipole interactions with the nitronate. The substituent at C6 would then reside in a pseudo-equatorial conformation in this 6-membered chelate 14, giving the stereoisomer as observed.
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Scheme 5
Three-step tandem concept for 1,3-diol synthesis.
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synthon. Our concept involves the addition of a homoallylic alcohol 5 to a suitable carbonyl compound 18 to obtain the corresponding hemiacetal-alkoxide (step 1). The formation of the electrophilic p-allylic complex (step 2) then leads to the generation of 17 which undergoes an intramolecular allylic substitution to yield the desired 1,3-allylic alcohol 16 in a suitably protected form (step 3).16 Notably, this sequence represents one of the rst examples of hemiacetal-alkoxides as nucleophiles in allylic substitutions.10m–p,17 The realization of this concept is depicted in Scheme 6.18 The most effective conditions for the selective synthesis of syn-1,3dioxanes of type 16 relied on homoallylic alcohol 10 in acetaldehyde as a co-solvent, with a slight excess of KHMDS (1.5 eq.) and catalytic amounts of [Pd(allyl)Cl]2 (10%) and PPh3 (30%) at room temperature, in toluene. This enabled an efficient entry to protected 1,3-syn-diols 16, with good stereoselectivities and yields. The substrate scope ranged from simple phenolic or benzylic, to aliphatic compounds. The general usefulness of this novel synthetic domino sequence for polyketide synthesis was demonstrated by the convergent synthesis of the northern fragment 28 of rhizopodin (Scheme 7). The necessary chiral homoallylic alcohols are readily accessible from simple starting materials, e.g. via the regioselective opening of terminal epoxides (21 to 24), or by the asymmetric allylation of aldehydes (22 to 24) with subsequent cross metathesis (viz 24 and 25 to 26). The pivotal reaction proceeded with high yield and selectivity, demonstrating the usefulness
Review
Scheme 7
and applicability of our approach. Importantly, the generated terminal alkene functionality may serve as a synthetic handle for the further elaboration of the target, as demonstrated in a fragment synthesis of macrolide RK-397 (not shown).18 3.3
Scheme 6 Concise synthesis of acetal-protected 1,3-syn-diols by a tandem hemiacetal/Tsuji–Trost reaction.
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Concise synthesis of the northern fragment 28 of
rhizopodin.
General concept and further applications
Based on these conformations of our novel type of domino sequence, a general concept for this tandem relay, relying on a nucleophilic substitution and Tsuji–Trost reaction, may be proposed. As shown in Scheme 8, it includes the coupling of different homoallylic nucleophiles, with X being oxygen, nitrogen or sulphur, to different types of electrophiles. These may be Michael acceptors 6 (le part), hetero-olens 34, e.g. imines or carbonyls (middle part) or allene homologues 37, e.g. cyanates or thiocyanates (right part) to give the corresponding 6-membered heterocycles 9, 36 or 38, respectively, with X being oxygen, nitrogen, sulphur or carbon. In all cases, these reactions should proceed by an anionic relay. For further proof, we turned our attention to 1,3-diamines and 1,3-aminoalcohols as prevalent structural motives in various bioactive natural products and medical compounds.19 In an effort to further evaluate the generality of our tandem combination of nucleophilic substitution and Tsuji–Trost reaction, we were particularly attracted to develop a more general approach to these compounds.20 Scheme 9 shows the implementation of this concept for the efficient synthesis of 1,3-syn and -anti tetrahydropyrimidinones (syn- and anti-42). Importantly, a modular and stereodivergent cyclization of urea-type substrates 41, by means of an intramolecular allylic substitution, was realized.21 This reaction proceeds with excellent yields (up to 99%) and stereoselectivities (>20 : 1). Notably, both the syn- and the anti-diastereomers can be obtained, with excellent asymmetric induction in a divergent manner from the same substrate, solely
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Scheme 8
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General domino concept based on a nucleophilic addition and Tsuji–Trost coupling.
Tandem processes for the stereoselective synthesis of 1,3-amino-alcohols.
Scheme 10
Scheme 9 Tandem processes for the stereoselective synthesis of synand anti-1,3-diamines.
controlled by solvent effects. The products of this pivotal conversion could be easily transformed to the corresponding free syn- and anti-amines 43. The general scope of our approach was then further conrmed in the synthesis of 1,3-syn oxazines 46 by a three step, sequential process of a hemi-aminalisation22, followed by a
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Tsuji–Trost reaction (Scheme 10).23 With this process, up to two new stereogenic centres can be generated, in a convergent and concise manner. Again, the starting materials are easily accessible and the product oxazines 46 may be transformed to the 1,3-aminoalcohols 47.
4 Tandem diyne-cyclization and regioselective openings The leupyrrins (4)5 are structurally unique myxobacterial metabolites, which exhibit potent biological activities against various fungi and eukaryotic cells. A key structural feature of these potent bioactive agents includes an unsymmetrically
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Review
substituted tetrahydrofuran core, with two exocyclic, E-congured double bonds, that remains without precedence and therefore, no synthetic strategy has been developed. Following a highly advantageous synthetic approach, this structural feature was envisioned to be derived by a three step sequence based on an oxidative diyne cyclization. In the past decades oxidative diyne cyclizations using lowvalent zirconocene and titanocene species, of type ‘Cp2M(II)’ have reached a prominent position for alkyne functionalization.24 Mechanistically, the reaction proceeds via intermediate metalla-cyclopentadienes 49, which can be cleaved with various reagents (Scheme 11). While symmetric cleavages by complete hydrolysis or dihalogenation are well established,25 a regioselective, stepwise opening through 50 has been much less advanced. A rst promising result, from the group of Takahashi in 1998, reported a selective monohalogenation of a zirconacyclopentadiene, bearing a mixed aliphatic-aromatic substitution pattern,26 based on the distinguishable basicity of both a-carbon atoms. Within our study programme the rst example for a regioselective opening of metallacycles with sterically similar demanding aliphatic side chains was realized. Importantly, this relies on an innovative use of remote directing groups. Such a sequence would allow a highly concise entry to the tetrahydrofuran core. Based on this synthetic design, a three-step, one-pot tandem process, including a zirconocene mediated cyclization of
unsymmetric aliphatic 1,6-diynes with a subsequent monohalogenation, was developed and mechanistically investigated.27 As shown in Scheme 12, this sequence includes a highly regioselective opening of zirconacyclopentadienes, of type 49, with NBS, which are derived by a cyclization from 1,6-diyne 52. This sequence enables a specic entry into monobrominated products 54 or 55. Notably, the selectivity prole may be inverted, i.e. the formation of 54 or 55, depending on the protective groups. This powerful proof of our concept of the critical inuence of a remote directing group was conrmed by DFT calculations, using Gaussian09 at the B3LYP level, revealing a pronounced tendency of the side chain functionality to interact with the metal (Scheme 12). The optimized geometries suggest that a stabilization may be caused by a diminished distance of the OMe group or the OPMB group to the metal center. Consequently, the Cp-rings are pushed closer to C15 or C18, which then leads to selective brominations. Importantly, this novel domino sequence was then applicable to an efficient synthesis of the authentic tetrahydrofuran core of the leupyrrins. Accordingly, the transformation of 58, which already bears all the necessary functionalities of the target molecule at C13, C14 and C21 in a suitable protected
Scheme 11 Regioselective opening of zirconacyclopentadienes: proposed one-pot synthesis of the furan core of the leupyrrins.
Scheme 12
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Tandem zirconocene-mediated diyne-cyclization and regioselective opening of zirconacyclopentadienes.
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form, was investigated. Importantly, this compound is easily accessible through etherication of 56 with 57 (Scheme 13). The adjacent zirconocene mediated, one pot cyclization regioselective opening of 59 again proceeded with high yields and selectivities, demonstrating the generality of our approach. Eventually, the required methyl group was installed by lithiation of 60 by means of tBuLi, followed by trapping of this lithiated species with Me2SO4, to give the desired C18 methylsubstituted diene 61 in a 53% yield, demonstrating the true
applicability of this sequential process in complex target synthesis.28
5 Sequential cross coupling methods 5.1
Convergent macrocyclization synthesis
Palladium-catalysed cross couplings are among the most important methods for C–C bond formation. Most prominently, the Suzuki and Stille coupling are omnipresent in complex target syntheses. In contrast, slightly fewer applications of Heck reactions in complex target synthesis have been reported, despite the obvious advantage of using a non-functionalized alkene and more specically, only a few examples of
Potent polyene macrolides etnangien and etnangien methyl ester and bis-metallated alkene synthons 70 and 71.
Fig. 2 Scheme 13 Concise synthesis of the furan core of the leupyrrins.
Scheme 14
Chemoselective cross-coupling strategy to the macrocyclic core of rhizopodin.
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intramolecular Heck reactions in the total synthesis of complex natural products have been applied.29 In an effort to further expand the scope of Heck reactions and to effectively use the unique advantage, as compared to the more conventional cross coupling reactions, we envisioned a sequential process relying on a Suzuki and Heck reaction for a highly concise synthesis of the macrocyclic core of rhizopodin (1),30 a potent G-actin polymerization inhibitor31 obtained from the myxobacterium Myxococcus stipitatus (Fig. 1).32 In detail, we envisioned a highly convergent approach with a sequential chemoselective crosscoupling strategy as a key step, exploiting the orthogonal reactivity of a dual functionalised precursor by sequential application of a Suzuki coupling and a Heck macrocyclization.33
Review
For the synthesis of the macrocyclic core, rstly acid 62 was esteried with the sterically hindered secondary alcohol of fragment 63, using Yamaguchi's reagent. The building block 64 bears both a terminal olen and a vinyliodine moiety, to enable the desired chemoselective cross coupling strategy (Scheme 14). As the rst step of our sequence, an intermolecular Suzuki coupling with boronate 65 proceeded smoothly at the vinyliodine terminus and afforded solely the desired E-isomer. Aer Yamaguchi esterication with acid 62, the terminal non-funtionalized alkene of 66 was then coupled to the terminal vinyliodide, in a Heck reaction. This cyclization required some optimisation in regards of the catalyst, additives and solvent and was found to proceed most effectively with Pd(OAc)2, K2CO3 and NBu4Cl in DMF, to give the macrocyclic core 67 in 77% yield and an E/Z-ratio of 5 : 1. In conclusion, the macrocyclic core 67 was prepared in only four steps from the elaborate building blocks 62, 63 and 65, with an overall yield of 64%, using a highly chemoselective crosscoupling strategy. Notably, this is one of the most advanced applications of intramolecular Heck reactions, demonstrating its power in complex natural product synthesis.29c,d,34 5.2 Hetero-bis-metallated alkenes as modular reagents towards olenic systems
General sequence for the synthesis of hetero-bis-metallated reagents 70 and 71.
Scheme 15
A key structural feature of the potent polyketide antibiotic etnangien29c,d,35 and polyketides in general are extended polyene fragments. For a convergent synthesis of such types of synthons,
Scheme 16 Modular, three-fragment coupling synthesis of the side chain analogues of etnangien based on hetero-bis-metallated alkenes.
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we envisioned the application and further development of hetero-bis-metallated alkenes, with conjugated and isolated olen subunits, which could be used in a sequential crosscoupling process (Fig. 2).36 As shown in Scheme 15, we were able to devise a practicable and general methodology for the synthesis of such type of reagents, bearing conjugated and isolated olen subunits, based on a straightforward three-step sequence, involving a hydrostannylation of alkynols 72,37 subsequent oxidation of the derived primary alcohols and a Boryl–Takai olenation38 of the aldehydes (Scheme 15). Demonstrating the utility of these reagents,39 we then constructed different polyene side chains of the polyketide etnangien in a highly concise and modular fashion (Scheme 16) via a convergent Stille/Suzuki–Miyaura cross-coupling sequence, being either fully or only partly conjugated. Notably, this enables a modular access also to more stable analogues, which may be important to devise a more stable analogue of these highly potent, but labile polyene antibiotics. It is expected that these novel bifunctional reagents will become effective building blocks for convergent polyene synthesis and analogues in modular and divergent approaches.
6
Conclusion and perspectives
In this review, we presented innovative strategies for the highly concise synthesis of key structural elements of polyketides. In detail, a novel domino concept based on a combination of a nucleophilic addition reaction and a Tsuji–Trost coupling has been devised and developed, which allows a highly concise entry into most diverse building blocks, including tetrahydropyrans, 1,3-amino alcohols, -diamines or -diols. Importantly, these methods proceed with high stereoselectivity and high degrees of asymmetric induction, purely based on substrate control, adding to the general usefulness of these procedures. Furthermore, a novel sequential process involving a zirconocene-mediated diyne-cyclization and highly regioselective opening of the intermediate metalcyclopentadienes has been developed as an efficient entry into complex target synthesis. Importantly, these two sequential processes combine several synthetic transformations in a one-pot process and thus, enable the rapid assembly of structural complexity. Additionally, an elegant method for the rapid assembly of an elaborate macrocycle was presented, using a chemoselective cross-coupling strategy as key step, exploiting the orthogonal reactivity of a dual functionalised precursor by sequential application of a Suzuki coupling and a Heck macrocyclization. Finally, heterobis-metallated alkenes were presented as modular reagents towards the synthesis of conjugated and isolated olenic systems, enabling a rapid access to side chain analogues of etnangien, in a highly concise and convergent manner. The true applicability of all these methods in complex target synthesis has been demonstrated and enabled a much more concise entry into the potent myxobacterial macrolides rhizopodin, etnangien and leupyrrin. It is expected that these novel sequences will be further explored and applied and speed up the process of complex polyketide synthesis. We anticipate that these methods
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will be further developed and applied in the synthesis of diverse polyketides and structurally related complex targets, which will be crucial for the advancement of these promising bioactive agents.
7
References
1 (a) C. Hertweck, Angew. Chem., Int. Ed., 2009, 48, 4688; (b) D. Menche, Nat. Prod. Rep., 2008, 25, 905; (c) K. J. Weissman and R. M¨ uller, Nat. Prod. Rep., 2010, 27, 1276; (d) M. Kretschmer and D. Menche, Synlett, 2010, 2989. 2 For a leading reference, see: K. Namba, H.-S. Jun and Y. Kishi, J. Am. Chem. Soc., 2004, 126, 7770. 3 For a leading reference, see: M. Dieckmann, M. Kretschmer, P. Li, S. Rudolph, D. Herkommer and D. Menche, Angew. Chem., Int. Ed., 2012, 51, 5667. 4 T. M. A. Gronewold, F. Sasse, H. L¨ unsdorf and H. Reichenbach, Cell Tissue Res., 1999, 295, 121. 5 (a) H. B. Bode, H. Irschik, S. C. Wenzel, H. Reichenbach, R. M¨ uller and G. H¨ oe, J. Nat. Prod., 2003, 66, 1203; (b) H. B. Bode, S. C. Wenzel, H. Irschik, G. H¨ oe and R. M¨ uller, Angew. Chem., Int. Ed., 2004, 43, 4163; (c) M. Kopp, H. Irschik, K. Gemperlein, K. Buntin, P. Meiser, K. J. Weissman, H. B. Bode and R. M¨ uller, Mol. BioSyst., 2011, 7, 1549. 6 (a) G. H¨ oe, H. Reichenbach, H. Irschik, D. Schummer, German Patent DE 196 30 980 A1: 1–7 (5.2. 1998); (b) H. Irschik, D. Schummer, G. H¨ oe, H. Reichenbach, H. Steinmetz and R. Jansen, J. Nat. Prod., 2007, 70, 1060; (c) D. Menche, F. Arikan, O. Perlova, N. Horstmann, W. Ahlbrecht, S. Wenzel, R. Jansen, H. Irschik and R. M¨ uller, J. Am. Chem. Soc., 2008, 130, 14234. 7 (a) B. M. Trost and C. S. Brindle, Chem. Soc. Rev., 2010, 39, 1600; (b) X. Ariza, J. Garcia, P. Romea and F. Urp´ı, Synthesis, 2011, 2175; (c) B. Schetter and R. Mahrwald, Angew. Chem., Int. Ed., 2006, 45, 7506; (d) Modern Methods in Stereoselective Aldol Reactions, ed. R. Mahrwald, WileyVCH, Weinheim, 2013. 8 J. Li and D. Menche, Synthesis, 2009, 2293. 9 For reviews on tandem reactions by several metal mediated processes, see: (a) J.-C. Wasilke, S. J. Obrey, R. T. Baker and G. C. Bazan, Chem. Rev., 2005, 105, 1001; (b) I. Ryu and N. Sonoda, Chem. Rev., 1996, 96, 177; (c) P. J. Parsons, C. S. Penkett and A. J. Shell, Chem. Rev., 1996, 96, 195; (d) L. F. Tietze, G. Brasche and K. M. Gericke, Domino Reactions in Organic Synthesis, 2006, Wiley-VCH, Weinheim; (e) S. Inuki, A. Iwata, S. Oishi, N. Fujii and H. J. Ohno, J. Org. Chem., 2011, 76, 2072; (f) S. Newman, J. Howell, N. Nicolaus and M. J. Lautens, J. Am. Chem. Soc., 2011, 133, 14916; (g) T. Vlaar, E. Ruijter and R. Orru, Adv. Synth.Catal., 2011, 353, 809; (h) T. Piou, L. Neuville and J. Zhu, Org. Lett., 2012, 14, 3760. 10 For general reviews, see: (a) B. M. Trost and C. Lee, Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley-VCH, New York, 2nd edn, 2000, p. 593; (b) A. Pfaltz and M. Lautens, Comprehensive Asymmetric Catalysis I–III, ed. E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Springer, Berlin, 1999, p. 833; (c)
Nat. Prod. Rep., 2014, 31, 456–467 | 465
View Article Online
Published on 23 December 2013. Downloaded by National Chung Hsing University on 20/03/2014 00:45:40.
NPR
11
12 13 14 15 16
17
18 19
B. M. Trost and M. Crawley, Chem. Rev., 2003, 103, 2921; (d) S. F¨ orster, G. Helmchen and U. Kazmaier, Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley, Hoboken, 3rd edn, 2010, p. 49; for addition of O-nucleophiles to p-allyl intermediates, see: ; (e) C. Morin and L. Ogier, Carbohydr. Res., 1998, 310, 277; (f) D. J. Covell and M. C. White, Angew. Chem., Int. Ed., 2008, 47, 6448; (g) J. S. Cannon, S. F. Kirsch and L. E. Overman, J. Am. Chem. Soc., 2010, 132, 15185; (h) A. N. Campbell, P. B. White, I. A. Guzei and S. S. Stahl, J. Am. Chem. Soc., 2010, 132, 15116; (i) A. D. Cuiper, R. M. Kellogg and B. L. Feringa, Chem. Commun., 1998, 655; (j) H. van der Deen, A. van Oeveren, R. M. Kellogg and B. L. Feringa, Tetrahedron Lett., 1999, 40, 1755; (k) H. Nakano, J. Yokoyama, R. Fujita and H. Hongo, Tetrahedron Lett., 2002, 43, 7761; (l) A. R. Haight, E. J. Stoner, M. J. Peterson and V. K. Grover, J. Org. Chem., 2003, 68, 8092; (m) R. Lakhmiri, P. Lhoste, B. Kryczka and D. Sinou, J. Carbohydr. Chem., 1993, 12, 223; (n) I. Frappa, B. Kryczka, P. Lhoste, S. Porwanskia and D. Sinou, J. Carbohydr. Chem., 1997, 16, 891; (o) I. Frappa, B. Kryczka, P. Lhoste, S. Porwanskia, D. Sinou and A. Zawisza, J. Carbohydr. Chem., 1998, 17, 1117; for a diastereoselective synthesis of acetal-protected syn 1,3-diols by a basecatalyzed intramolecular conjugate addition of hemiacetalderived alkoxide nucleophiles, see: ; (p) D. A. Evans and J. A. Gauchet-Prunet, J. Org. Chem., 1993, 58, 2446. (a) B. M. Trost, S. M. Silverman and J. P. Stambuli, J. Am. Chem. Soc., 2007, 129, 12398; (b) R. Shintani, S. Park, W.-L. Duan and T. Hayashi, Angew. Chem., Int. Ed., 2007, 46, 5901; (c) R. Shintani, M. Murakami, T. Tsuji, H. Tanno and T. Hayashi, Org. Lett., 2009, 11, 5642; (d) F. J. Williams and E. R. Jarvo, Angew. Chem., Int. Ed., 2011, 50, 4459. For reviews, see: (a) P. A. Clarke and S. Santos, Eur. J. Org. Chem., 2006, 2045; (b) H. Fuwa, Heterocycles, 2012, 85, 1255. (a) C. F. Nising and S. Br¨ ase, Chem. Soc. Rev., 2008, 37, 1218; (b) C. F. Nising and S. Br¨ ase, Chem. Soc. Rev., 2012, 41, 988. L. Wang, P. Li and D. Menche, Angew. Chem., Int. Ed., 2010, 49, 9270. L. Wang and D. Menche, J. Org. Chem., 2012, 77, 10811. A related strategy has been reported by the group of Cossy using cyclic borates. However, in this study the 1,3-diols were obtained with only poor diastereoselectivities: J. Cluzeau, J. Capdevieille and J. Cossy, Tetrahedron Lett., 2005, 46, 6945. For an alternative domino sequence for 1,3-anti diol synthesis, see: M. Dieckmann and D. Menche, Org. Lett., 2013, 15, 228. L. Wang and D. Menche, Angew. Chem., Int. Ed., 2012, 51, 9425. For the synthesis of amino alcoholes see: (a) F. Koehler, H. J. Gais and G. Raabe, Org. Lett., 2007, 9, 1231; (b) D. N. Zalatan and J. Du Bois, J. Am. Chem. Soc., 2008, 130, 9220; (c) B. Weiner, A. Baeza, T. Jerphagnon and B. L. Feringa, J. Am. Chem. Soc., 2009, 131, 9473; (d) G. T. Rice and M. C. White, J. Am. Chem. Soc., 2009, 131, 11707; (e) S. M. Paradine and M. C. White, J. Am. Chem. Soc., 2012, 134, 2036; (f) R. A. T. M. van Benthem,
466 | Nat. Prod. Rep., 2014, 31, 456–467
Review
20
21 22
23 24
25
26 27 28 29
30
H. Hiemstra, J. J. Michels and W. N. Speckamp, J. Chem. Soc., Chem. Commun., 1994, 357. For a recent review on chiral amine synthesis, see: T. C. Nugent and M. El-Shazly, Adv. Synth. Catal., 2010, 352, 753. For previous work from our group on direct stereoselective amine synthesis, see: (a) D. Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter and S. Rudolph, Org. Lett., 2006, 8, 741; (b) D. Menche, F. Arikan, J. Li and S. Rudolph, Org. Lett., 2007, 9, 267. M. Morgen, S. Bretzke, P. Li and D. Menche, Org. Lett., 2010, 12, 4494. For a domino reaction involving a hemiaminalization, see: T. Urushima, D. Sakamoto, H. Ishikawa and Y. Hayashi, Org. Lett., 2010, 12, 4588. B. Tang, L. Wang and D. Menche, Synlett, 2013, 24, 625. For Ti-mediated examples, see: (a) W. A. Nugent and J. C. Calabrese, J. Am. Chem. Soc., 1984, 106, 6422; (b) W. A. Nugent, D. L. Thorn and R. L. Harlow, J. Am. Chem. Soc., 1987, 109, 2788. For Zr-mediated examples, see: ; (c) E. Negishi, F. E. Cederbaum and T. Takahashi, Tetrahedron Lett., 1986, 27, 2829; (d) E. Negishi, S. J. Holmes, J. M. Tour, J. A. Miller, F. E. Cederbaum, D. R. Swanson and T. Takahashi, J. Am. Chem. Soc., 1989, 111, 3336; (e) M. I. Kemp, S. J. Coote and R. J. Whitby, Synthesis, 1998, (Sup. 1), 557; (f) R. T. Chen and K. T. Wong, Tetrahedron Lett., 2002, 43, 3313. (a) S. L. Buchwald and R. B. Nielsen, Chem. Rev., 1988, 88, 1047; (b) S. L. Buchwald and R. B. Nielsen, J. Am. Chem. Soc., 1989, 111, 2870. H. Ubayama, Z. Xi and T. Takahashi, Chem. Lett., 1998, 27, 517. T. Debnar, S. Dreisigacker and D. Menche, Chem. Commun., 2013, 49, 725. T. Debnar, T. Wang and D. Menche, Org. Lett., 2013, 15, 2774. (a) A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945; (b) M. Christmann, U. Bhatt, M. Quitschalle, E. Claus and M. Kalesse, Angew. Chem., Int. Ed., 2000, 39, 4364; (c) P. Li, J. Li, F. Arikan, W. Ahlbrecht, M. Dieckmann and D. Menche, J. Am. Chem. Soc., 2009, 131, 11678; (d) P. Li, J. Li, F. Arikan, W. Ahlbrecht, M. Dieckmann and D. Menche, J. Org. Chem., 2010, 75, 2429. For fragment syntheses see: (a) Z. Cheng, L. Song, Z. Xu and T. Ye, Org. Lett., 2010, 12, 2036; (b) T. Chakraborty, K. K. Pulukuri and M. Sreekanth, Tetrahedron Lett., 2010, 51, 6444; (c) T. K. Chakraborty, M. Sreekanth and K. K. Pulukuri, Tetrahedron Lett., 2011, 52, 59; (d) K. K. Pulukuri and T. K. Chakraborty, Org. Lett., 2012, 14, 2858; (e) M. Kretschmer and D. Menche, Org. Lett., 2012, 14, 382. For synthesis of the originally proposed monomeric structure see: K. C. Nicolaou, X. Jiang, P. J. Lindsay-Scott, A. Corbu, S. Yamashiro, A. Bacconi and V. M. Fowler, Angew. Chem., Int. Ed., 2011, 50, 1139. For total syntheses see: ; (f) M. Dieckmann, M. Kretschmer, P. Li, S. Rudolph, D. Herkommer and D. Menche, Angew. Chem., Int. Ed., 2012, 51, 5667; (g) S. M. Dalby, J. Goodwin-Tindall and Paterson, Angew. Chem., Int. Ed.,
This journal is © The Royal Society of Chemistry 2014
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Review
Published on 23 December 2013. Downloaded by National Chung Hsing University on 20/03/2014 00:45:40.
31
32
33 34
2013, 52, 6517; (h) M. Kretschmer, M. Dieckmann, P. Li, S. Rudolph, D. Herkommer, J. Troendlin and D. Menche, Chem.–Eur. J., 2013, 19, 15993. For reviews on actin-binding macrolides, see: (a) K.-S. Yeung and I. Paterson, Angew. Chem., Int. Ed., 2002, 41, 4632; (b) J. S. Allingham, V. A. Klenchin and I. Rayment, Cell. Mol. Life Sci., 2006, 63, 2119. (a) R. Jansen, H. Steinmetz, F. Sasse, W.-D. Schubert, G. Hagel¨ uken, S. C. Albrecht and R. M¨ uller, Tetrahedron Lett., 2008, 49, 5796; (b) N. Horstmann and D. Menche, Chem. Commun., 2008, 5173; (c) G. Hagel¨ uken, G. Albrecht, R. Jansen, H. Steinmetz, D. Heinz, M. Kalesse, F. Sasse and W.-D. Schubert, Angew. Chem., Int. Ed., 2009, 48, 595. M. Dieckmann, S. Rudolph, S. Dreisigacker and D. Menche, J. Org. Chem., 2012, 77, 10782. (a) D. Menche, J. Hassfeld, J. Li and S. Rudolph, J. Am. Chem. Soc., 2007, 129, 6100; (b) D. Menche, J. Hassfeld, J. Li, K. Mayer and S. Rudolph, J. Org. Chem., 2009, 74, 7220.
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35 D. Menche, P. Li and H. Irschik, Bioorg. Med. Chem. Lett., 2010, 20, 939. 36 (a) R. S. Coleman and M. C. Walczak, Org. Lett., 2005, 7, 2289; (b) R. S. Coleman, X. Lu and I. Modolo, J. Am. Chem. Soc., 2007, 129, 3826; (c) F. Lhermitte and B. Carboni, Synlett, 1996, 377; (d) R. S. Coleman, M. C. Walczak and E. L. Campbell, J. Am. Chem. Soc., 2005, 127, 16038; (e) R. S. Coleman and M. C. Walczak, J. Org. Chem., 2006, 71, 9841; (f) R. S. Coleman and X. Lu, Chem. Commun., 2006, 423. 37 A. Darwish, A. Lang, T. Kim and J. M. Chong, Org. Lett., 2008, 10, 861. 38 K. Takai, N. Shinomiya, H. Kaihara, N. Yoshida and T. Moriwake, Synlett, 1995, 963. 39 (a) M. Altendorfer and D. Menche, Chem. Commun., 2012, 48, 8267; (b) M. Altendorfer, A. Raja, F. Sasse, H. Irschik and D. Menche, Org. Biomol. Chem., 2013, 11, 2116; (c) M. Altendorfer, H. Irschik and D. Menche, Bioorg. Med. Chem. Lett., 2012, 22, 5731.
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