Chemical Society Reviews
Cascade Polycyclizations in Natural Product Synthesis
Journal: Chemical Society Reviews
Manuscript ID CS-SYN-02-2015-000105.R2
Article Type: Tutorial Review
Date Submitted by the Author: 13-Dec-2015
Complete List of Authors: Ardkhean, Ruchuta; University of Oxford, Chemistry Research Laboratory Caputo, Dimitri; University of Oxford, Chemistry Research Laboratory Morrow, Sarah; University of Oxford, Chemistry Research Laboratory Shi, Heyao; University of Oxford, Chemistry Research Laboratory Xiong, Yaoyao; University of Oxford, Chemistry Research Laboratory Anderson, Edward; University of Oxford, Chemistry Research Laboratory
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Chemical Society Reviews RSC Publishing
Tutorial Review
Cascade Polycyclizations in Natural Product Cite this: DOI: 10.1039/x0xx00000x Synthesis
R. Ardkhean, D. F. J. Caputo, S. M. Morrow, H. Shi, Y. Xiong and E. A. Anderson* Received 00th January 2012, Accepted 00th January 2012 Cascade (domino) reactions have an unparalleled ability to generate molecular complexity DOI: 10.1039/x0xx00000x from relatively simple starting materials; these transformations are particularly appealing when www.rsc.org/ multiple rings are forged during this process. In this tutorial review, we cover recent highlights in cascade polycyclizations as applied to natural product synthesis, including pericyclic, heteroatom mediated, cationic, metal catalyzed, organocatalytic, and radical sequences . Introduction Scheme 1) of (–) PF 1018,9 a tricyclic insecticide isolated from Humicola sp. , is notable for its unusual Diels Alder termination Natural product total synthesis represents a pinnacle of step following a tetraene 8 π electrocyclization, rather than the achievement and ambition in organic chemistry, and is arguably 6π electrocyclization usually observed with monocyclic fundamental to the successful commercial development of cyclooctatrienes.8 The cascade is triggered by Stille coupling of natural products or their derivatives as bioactive agents. 1 3 Not vinyl iodide 2 with vinyl stannane 3 to generate tetraene 4. 8π least due to the advent of new catalytic processes (such as C–H electrocyclization and subsequent intramolecular Diels Alder activation, organocatalysis, and photoredox chemistry, amongst (IMDA) cycloaddition delivered tricycle 1 in 32% yield as a others), combined with the evergreen creativity of the synthetic single diastereomer. This reflects strong torquoselectivity (i.e., organic chemist, can truly concise and efficient routes to the rotational directionality of the conrotatory cyclization), complex bioactive natural products be realized. Chief among arising from a specific helical arrangement of the cyclizing the armaments of the modern synthetic practitioner are cascade tetraene. The avoidance of the competing 6 π reaction may in (domino) reactions – transformations that by their very nature part be due to the high degree of torsional strain that might arise not only achieve significant increases in molecular complexity between the C19 methyl and enoate sidechain in the required and reductions in overall step count, but also demonstrate planar arrangement of the 8 membered ring. synthetic elegance and creativity.4 In this review, we highlight A remarkable intermolecular / intramolecular Diels Alder achievements at the frontier of this field, where cascade cascade has been realized in the Liu group's bioinspired 14 step reactions are deployed to prepare polycyclic frameworks, synthesis of (–) bolivianine ( 5, Scheme 2), 10, 11 the heptacyclic embedded in the setting of complex molecule synthesis. As in skeleton and nine contiguous stereocentres of which pose a the style of a previous coverage, 5 these domino processes are
loosely divided into themes of pericyclic, heteroatom mediated, MeO2C MeO2C SnMe 3 cationic, metal catalyzed, organocatalytic, and radical cascades. The aim of this review is therefore not to provide a comprehensive coverage, 6 but to present the reader with a 3 I OTBS OTBS flavour of the state of the art, as well as to describe impressive Pd(PPh 3)4 (10 mol%), CuTC (1.1 equiv.), new developments and technologies in each of these themes. DMF, 65→125 °C 2 4 Pericyclic cascades
OTBS Much continues to be learnt from Nature's use of pericyclic 8π OTBS MeO2C MeO2C [4+2] cascades to assemble complex natural product frameworks, and 1919 32% synthetic chemists have long recognized that biomimetic cascades7 enable powerful retrosynthetic disconnections, with electrocyclic components commonplace in these sequences. 8 1 The Trauner group's synthesis of the core ring structure (1, Scheme 1. Stille/8π/IMDA cascade towards PF-1018 (Trauner and co-workers).
This journal is © The Royal Society of Chemistry 2013 J. Name ., 2013, 00 , 1-3 | 1 Chemical Society Reviews Page 2 of 13 Journal Name ARTICLE significant and attractive synthetic proposition. The final step of NHTs this synthesis is the reaction of onoseriolide aldehyde 6 (itself N NaH, toluene, N thought to be an important intermediate in the biosynthesis of N OTBDPS reflux bolivianine) with β (E) ocimene ( 7, a compound again detected in the producing plant, Hedyosmum angustifolium ). These two TBDPSO components undergo a Diels Alder / intramolecular hetero 11 12 Diels Alder cascade via intermediate 8 to give the natural product in 52% yield as a single diastereomer. This selectivity [3+2] is rationalized by an endo-selective cycloaddition of the diene N N on the bottom face of the onoseriolide framework ( 9). Although retro [3+2] the first step of this cascade required elevated temperatures and H O the presence of the sidechain aldehyde to activate the TBDPSO TBDPS dienophile, it is notable that the second Diels Alder process was 14 13 found to occur spontaneously at room temperature, adding 87% [3+2] support to the possibility that this synthesis indeed resembles the biosynthetic pathway. This work is particularly impressive H H given the challenge posed by an intermolecular cycloaddition 10 steps initiation step. HO O O OTBDPS O H 15 10: (–)-crinipellin A O O O 7 O Scheme 3. [3+2] cycloaddition cascade, via a trimethylenemethane diyl, in the H synthesis of (–)-crinipellin A (Lee and co-workers). H toluene, 150 °C, O sealed tube, 2 h O 52% 9 that features a bridgehead double bond. The group identified an 6 Ireland Claisen / Cope rearrangement ring contraction strategy 14 inter- as a possible means to access this challenging structure. To molecular H H test this, macrolactone 17 was efficiently synthesized in just 4 DA O IMHDA H H steps from 18 , via a twofold alkene metathesis. Treatment of 17 O O H with chlorodimethylphenylsilane and DBU then gives silyl enol H H ether 19 . Through the illustrated boat conformation, Ireland O O O 8 5: (–)-bolivianine Scheme 2. Biomimetic cycloaddition cascade in the synthesis of (–)-bolivianine i-Pr (Liu and co-workers). O 4 steps H O Non biomimetic pericyclic cascades also offer excellent 1. Me 2PhSiCl, O DBU, PhCF3, synthetic opportunities. In this context, an elegant 140 °C, 24 h TIPSO polycyclization featuring two unusual cycloadditions has been OTIPS OH 18 17 developed by the Lee group in a landmark total synthesis of (–) crinipellin A (10, Scheme 3). 12 The key cycloaddition i-Pr TIPS O H sequence is initiated by treatment of hydrazone 11 with sodium O hydride, which promotes formation of diazo compound 12 . A i-Pr H O spontaneous [3+2] cycloaddition of 12 with the pendent allene OSiMe 2Ph PhMe 2SiO PhMe 2SiO leads to diazene intermediate 13 (as an inconsequential mixture O OSiMe 2Ph of diastereomers), extrusion of nitrogen from which gives TIPS 20 19 trimethylenemethane diyl 14 . Despite high steric congestion, a 64% 2. 1N HCl (3 steps) 3. TMSCHN2 OH further [3+2] cycloaddition of this intermediate gives OH tetraquinane 15 in an outstanding 87% yield as a single i-Pr diastereomer; a pseudo-equatorial positioning of substituents H likely controls this stereochemical outcome. This creative step H CO 2Me forges the crinipellin skeleton and sets three stereocentres, H H H H including two contiguous quaternary carbon atoms. A final 'pericyclic' example is found in Leighton and co TIPSO 21 HO 16 : cyclocitrinol O O workers' expedient route to the steroidal core of cyclocitrinol Scheme 4. Cascade pericyclic ring contraction route to the core of cyclocitrinol 13 (16 , Scheme 4). The central challenge in the construction of (Leighton and co-workers). this polycyclic skeleton lies with the strained [4.4.1] bicycle
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OH OH O CbzHN CbzHN
N3 PyHBr 3, K 2CO 3, N3 HN N HN N H H CH 2Cl 2 / H 2O (1:1), rt, 1 h H 30 : (±)-rengyolone O HO Br MsO 24 OMs 23 homochiral oxa-Michael heterochiral oxa-Michael
K2CO 3 (0.1 equiv.), DCE, 70 οC, 18 h OH OH O O O O
N3 HN N3 N3 O HN HN Br Br H H N N Br Br Br H O H O O O Cbz H N N N N O O Cbz H Cbz H HO HO
OMs Michael Michael 27 26 OMs 25 OMs O OH O H O H H H H N3 N O HN HN H O O NH 2 H Br O H CbzN N H N N NH H O O O Br 2 O OH HO HO H 28 22 : decarbamoyl α-saxitoxinol 29 : (±)-incarviditone (19%) Scheme 5 . Double-bromocyclization approach to decarbamoyl α-saxitoxinol O O (Sawayama and Nishikawa). OH O O O Claisen rearrangement of 19 affords 20 , which then undergoes a H Aldol H strain relieving Cope rearrangement to give the tricyclic H O HH O O O product 21 . The presence of an isopropyl group on the lactone H H H H ring is crucial to avoid side reactions; through this sequence, a OH OH 64% yield of 21 is obtained after hydrolysis and esterification. 31 : (±)-incarvilleatone (23%) 32 Scheme 6. Homochiral and heterochiral oxa-Michael initiated cascades to (±)- Heteroatom-mediated cascades incarviditone and (±)-incarvilleatone (Lawrence and co-workers).
Heteroatoms continue to offer an excellent means to promote cascade in which the racemic natural product (±) rengyolone 30 cascade polycyclizations in natural product synthesis, and four undergoes homochiral dimerization via an oxa Michael / examples have been selected that illustrate recent developments Michael addition to afford 29 . However, formed in equal in this field. Firstly, a novel double bromocyclization has been quantity in this reaction is product 31 , which arises from a employed by Sawayama and Nishikawa to establish the cyclic separate three step cascade beginning with a heterochiral guanidine pyrrolidine structure found in decarbamoyl α dimerization of (±) rengyolone – a pathway that is entirely saxitoxinol (22, Scheme 5), a non toxic analogue of saxitoxin reasonable given a racemic starting material. Here, the produced by the cyanobacterium Lyngyba wollei .15 In a conformation of Michael adduct 32 is such that a further aldol biphasic medium of water / dichloromethane, a stereospecific cyclization is possible (leading to 31). In fact, this compound cascade cyclization is initiated by generation of a bromenium itself turned out to be a natural product (incarvilleatone) whose ion 23 upon treatment of alkyne 24 with pyridinium tribromide. existence was disclosed only during the preparation of the This highly reactive intermediate undergoes intramolecular synthetic manuscript. Thus, depending on the combination of nucleophilic displacement by the guanidine residue, leading to two equivalent, or different enantiomers of rengyolone (30 ), enamine 25 . Formation of a bromonium ion 26 from this different natural product structures are accessed – a fascinating enamine then promotes the construction of the bridging phenomenon that we will return to later in this review. oxacycle, giving spiroaminal ether intermediate 27 . Finally, an Heteroatom mediated epoxide ring opening cascades are an intramolecular N alkylation concludes the cascade cyclization ideal biomimetic tactic for the synthesis of poly oxacyclic 17 19 to afford the tricyclic skeleton 28 . Although the oxacyclic ring natural products. Although it is generally recognized in is eventually opened, this aminal ether later facilitates these reactions that exo ring opening ( via a 'spiro' transition construction of the second guanidine ring in the natural product. state) is usually kinetically favoured over endo ring opening Domino biomimetic sequences can often lead to (via a 'fused' transition state), much synthetic effort has been serendipitous discoveries. The first total synthesis of (±) directed towards controlling this regioselectivity problem. Two incarviditone (29 , Scheme 6), reported by Lawrence and co examples are presented here that offer new solutions through workers,16 exploits an elegant biomimetic heteroatom mediated the innovative generation of epoxonium ions; the challenge
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TBDPSO TBDPSO hν, TBDPSO BocO PF 6 BocO Ph N BocO 35 (0.5 equiv.) –Ph 2HC• Ph O O O2, Na 2S2O3, NaOAc, O O OMe DCE / toluene (5:1), O O OMe OMe 34 rt, 3 h 36 37
O O O H OTBDPS O O O H OH 45% O O O OH O O O (75% brsm) O H H MeO H H OTBDPS MeO O O 33 : lactodehydrothyrsiferol 39 38 Scheme 7. Oxidative epoxide-opening cyclization approach to lactodehydrothyrsiferol (Floreancig and co-workers). faced with such chemistry is the selective activation of the photochemically mediated oxidation of a homobenzhydryl desired epoxide in a polyepoxide substrate, which can be ether. 21 The reaction initiates with 34 , which through single problematic when 'traditional' Lewis acids are employed. electron transfer to the excited state of quinolinium cation 35 The first example is a total synthesis of the protein generates intermediate radical cation 36 .22 This spontaneously phosphatase 2A inhibitor lactodehydrothyrsiferol (33, Scheme loses a benzhydryl radical, leading to oxocarbenium ion 37 , 7), reported by the Floreancig group. 20 The key regioselective attack onto which by the proximal epoxide gives epoxonium epoxonium ion generating transformation involves a ion 38 . This in turn undergoes a double cyclization cascade with the next epoxide and the tert-butoxycarbonate (with TMS concomitant loss of a tert butyl cation), to afford tricycle 39 . OBoc Teurilene ( 40 , Scheme 8) is a cytotoxic triterpene polyether (OC) Co O O O 3 biosynthetically linked to the thyrsiferol family. Martín and co Co (CO)3 workers have developed a mild cascade route to the teurilene OH 23 24 41 oxatricyclic ring system that employs a Nicholas reaction. 1. SiO2, CH 2Cl 2, rt, 76 h Thus, exposure of the dicobalt hexacarbonyl complexed TMS propargylic alcohol 41 to silica gel in dichloromethane at room temperature provides a sufficiently acidic reaction medium to (OC)3Co Co promote ionization, epoxonium ion formation ( 42 ), and cascade (CO)3 O cyclization of the tris-epoxide. Oxidative liberation of the OBoc O O alkyne by CAN mediated cobalt decomplexation afforded tris tetrahydrofuran 43 in 75% yield. The formation of an epimeric 42 OH 2 mixture at the propargylic position was not problematic, as an isomerization later established the desired configuration. 75% (2 steps) 2. CAN, acetone, 0 οC, 1 h Interestingly, and contrary to the lactodehydrothyrsiferol example, the authors did not observe an additional cyclization of the Boc group onto the intermediate cation. O O H H O OH H H Cationic cascades
43 TMS OBoc Cation induced polyene cyclizations offer a powerful means to construct complex polycyclic structures via multiple carbon carbon bond formations. Such pathways are well known in O Nature; however, controlling the regio and stereochemistry of O H H O HO OH these processes in a synthetic context is highly challenging. A H H landmark achievement in this field is the report by Ishihara and co workers of the first example of a highly enantioselective
40 : teurilene terpene halopolycyclization, employing chiral phosphoramidite promoters (Scheme 9a). 25 In the illustrated example, Scheme 8. Nicholas reaction-triggered epoxide-opening cascade in the synthesis phosphoramidite 44 is converted into a chiral halogenating of teurilene (Martín and co-workers). agent 45 upon treatment with N-iodosuccinimide, which
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Scheme 9. Halonium ion-initiated polycyclizations ( a Ishihara, b Snyder, and co-workers).
enables enantioselective iodonium ion formation (46 ), and approach – it involves a Lewis acid promoted epoxide opening subsequent cationic cascade cyclization to tetracycle 47 . Due to to promote cyclization – and also several Wagner Meerwein the formation of some monocyclic intermediates, exposure of rearrangements. However, key to the success of this work is
the crude reaction mixture to chlorosulfuric acid (ClSO 3H) sequestration of the Lewis acid counteranion at the tail end of ensures complete conversion to fully cyclized products, with 47 the terpenoid, which is achieved through strong aluminium isolated in good yield (52%) and excellent stereoselectivity heteroatom bonds. This separates the counterion from the (99% ee, 94:6 dr ). The use of a sterically hindered developing cationic centres, and thus prevents undesirable phosphoramidite and an apolar solvent (toluene) was crucial to elimination (E1) or cation anion recombination processes. the success of this chemistry: it was proposed that key complex Following complexation of epoxide 53 by the 45 may exist as a tight ion pair, with a relatively strong aluminium(III) Lewis acid, ring opening at the allylic position hydrogen bond to the succinimide ion restricting P–N bond leads to tertiary cyclohexylalkyl cation (54 →55 ), which rotation, thus enhancing the level of stereocontrol. undergoes a 1,2 hydride shift to afford cyclohexyl cation 56 . Snyder and co workers' studies on polyene cyclizations This cation is now appropriately disposed to undergo attack by induced via more elusive chloronium and bromonium ions have the remaining alkenyl chain, a non diastereoselective process led to the synthesis of several natural products,26 including (±) that affords epimeric mixtures of the spirocyclic tertiary cations peyssonoic acid A (48 Scheme 9b). Being a marine natural 57 and 58 . In both cases, the cation is positioned in proximity to product, a bromonium ion initated cyclization has clear the cyclohexene ring, and through a final cyclization process biosynthetic relevance. However, a key design element for this affords cations 59 and 60. The predominant final products 61 reactivity is the need to inhibit the nucleophilicity and basicity and 62 (the β cedrene and β funebrene skeletons) then arise of the counteranion, which could otherwise compete in the from a 1,2 hydride shift driven by carbonyl formation. The lack bromonium ion ring opening. This is achieved by the use of of stereoselectivity in this reaction is interesting, and may in bromodiethylsulfonium bromopentachloroantimonate ( 49 ) to part arise from the enforced stepwise cyclization pathway in the promote formation of bromonium ion 50 from polyene 51 , TH manifold, compared to the chair like conformations that are capture of which by the two alkenes and phenolic ether gives accessible in HT cyclizations. 28 The laboratory realization of 52 . This cyclization, which builds three rings in a single these complex biosynthetic pathways is nonetheless an operation, is only three steps from the natural product 48 . impressive and informative achievement. Terpene cyclizations can be classified by the direction of The Aspidosperma alkaloids have long attracted the charge propagation. Biomimetic total syntheses invariably attention of synthetic chemists due to their bioactivities and employ head to tail (HT) cyclizations, in which the cation is fascinating diversity of structures, which offer many formally transmitted from the branched ‘head’ of the terpene to opportunities for cascade cyclizations. 29 In this context, Zhu the nucleophilic ‘tail’. However, the total synthesis of the and co workers have recently developed a unified oxidation / strained funebrene and cedrene natural products by Pronin and reduction / cyclization sequence that constructs the polycyclic Shenvi (Scheme 10) illustrates an intriguing realization of the core of the cytotoxic Aspidosperma alkaloid (±) goniomitine relatively unexplored tail to head (TH) cyclization mode.27 The (63 , Scheme 11) along with four other structurally related chemistry has many of the characteristics of a traditional HT members of the family. 30 The one pot cyclization commences
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dr = 1:1 MeAlCl2, L3Al O BnO Me 2AlCl, OBn O CH 2Cl 2 / hex, −78 °C Et O , NaHCO , MeOH, 11 54 3 3 H N O 6 −78 °C; 2 Head 6 1 53 26% NO Et 2 Me S, −78 °C→rt; Tail 2 O Zn, CaCl 2, reflux, 2 h C–C N 3 NH O O 64 65 2 L3Al L3Al + +H −2H 2O C–C 1,2-hydride shift OR 11 OBn 6 6 H H N N 80% H 56 55 H Et Et HN HN 1 1,2-H 66 : R = Bn sodium naphthalenide, C–C H H shift H 63 : (±)-goniomitine (R = H) –20 °C, 15 min, 65% 11 H Scheme 11 . Oxidation / reduction / cyclization sequence towards (±)- H CHO goniomitine (Zhu and co-workers). OAlL3 L3AlO 57 59 61 : ( ±)- β-cedrene framework H H readily achieved by temporary functionalization of the amines 1 H 1,2-H as tert-butyl carbamates 71b and 72b ; regioselective acetylation C–C shift 11 of 71b yielded (+) flabellidine 67 , or IBX mediated oxidation H furnished (−) lycodine 68 . This synthetic ideal was H OAlL CHO contemporaneously utilized by Smith and co workers in a L AlO 3 32 3 58 60 62 : ( ±)- β-funebrene synthesis of the related natural product (−) gephyrotoxin. framework Scheme 10. Tail-to head biomimetic assembly of the β-cedrene and β-funebrene NBnBoc O O NBnBoc natural products (Pronin and Shenvi).
with ozonolysis of 64 to generate a diketone, with an in situ 69 1. (+)-CSA, CH2Cl 2, 50 °C, 61% zinc mediated reduction of the nitro group and azide yielding 2. Pd(OH)2/C, H 2, Boc2O, EtOAc / MeOH, rt, 76% H the key diamine intermediate 65. Under the moderately acidic reaction conditions, this triggers a double condensation, and H Me then cyclization of the resulting indole nitrogen atom onto the pendent iminium ion with exclusive formation of a cis-fused NBn NBn BnN BnN ring junction. A Birch reduction is employed on compound 66 to effect debenzylation, which affords the natural product 63 . 70a 70b The Lycopodium alkaloids (e.g. flabellidine 67 , and H lycodine 68 , Scheme 12) have also been a subject of some H interest, again by virtue of their biological activities and unique R R 71a , 72a (3:1) bicyclo[3.3.1]nonane that are fused to two peripheral piperidine N N R = Bn 31 71b , 72b (2.6:1) rings. Takayama and co workers have developed an NR RN R = Boc impressive biomimetic tricyclization cascade to access these 71 72 two natural products from a minimally functionalized, acyclic starting material 69 . The cyclization is initiated by deprotection 1. TFA, CH2Cl 2, rt 1. TFA, CH2Cl 2, rt ο 2. AcCl, Et 3N, THF 2. IBX, DMSO, 45 C of the two terminal amines in 69 , which spontaneously cyclize 88% (2 steps) 62% (2 steps) to give the enamine iminium ion intermediate 70 . The diastereoselectivity of the ensuing Michael cyclization is proposed to be controlled by the single pre installed stereogenic Ac N centre, where conformer 70b is disfavoured by a steric clash N between the pseudo-axial methyl group and the forming ring NH NH system, which is not present in conformer 70a . The conjugated iminium ion formed from this Michael addition is then in turn 67 : ( +)-flabellidine 68 : ( −)-lycodine trapped by the enamine of the other ring, leading (after further Scheme 12. Iminium ion / enamine biomimetic cascade route to (+)-flabellidine tautomerization) to tetracycle 71a , and its diastereomer 72a and (–)-lycodine (Takeyama and co-workers). (61%, 71a :72a = 3:1). Separation of these compounds was most
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Metal-catalyzed cascades NCMe PF 6 Au Metal catalyzed reactions offer an exceptional means to (t-Bu)2P (2 mol%) a) 80 engineer cascade processes, due to their high functional group OBn [AuL] tolerance, orthogonality to other reaction manifolds, and most BnO Ph importantly their ability to construct a wide variety of complex structures through unique but highly selective mechanistic H pathways. In many cases, metal catalysis is synonymous with b) 81 high atom economy, 33 particularly for cycloisomerization 79 OH reactions,34 where a number of applications in the synthesis of [AuL] natural products have been reported in recent years. path The explosion of research in gold catalysis has inevitably a) 35, 36 H H led to some elegant synthetic demonstrations; two neat, rt, examples have been selected which highlight the level of fine 5 min tuned molecular complexity that can be achieved with this 83 OBn OBn 82 metal. The first involves two syntheses of the sesquiterpene (–) englerin B (73 , Scheme 13) reported concurrently by the [AuL] Echavarren 37 and Ma groups.38 These syntheses vary only in the path b) nature of the propargylic substituent in enyne 74 , which leads H H to different synthetic endgames. These cascades initiate by Allyl alcohol (20 equiv.), AllylO 85 AllylO 84 –30 °C, 15 min complexation of the alkyne in 74 to the gold(I) cation, which triggers cyclopropane formation ( 75 ) via alkenylgold species Scheme 14. Nucleophile-tuned approach to three aromadendrane natural 76 . Nucleophilic ring opening of the cyclopropane by the products (Echavarren and co-workers). carbonyl leads to oxocarbenium ion 77 ; a deaurative Prins type cyclization completes the tricyclic core 78 of englerin B. of the benzyloxy group to give carbenoid 82 (path a), and then Following this work, the Echavarren group published tricycle 83 , a precursor to (–) 4β,7 α aromadendranediol and syntheses of three aromadendrane natural products (Scheme (–) epiglobulol. Alternatively, equivalent reaction in the 14). 39 This more recent report is noteworthy for the exquisite presence of an excess of allyl alcohol results in intermolecular control over the stereochemical outcome of the gold catalyzed ring opening of 81 to the epimeric carbenoid 84 / tricycle 85 cascade that is achieved by simple but logical variation of the (path b), en route to (–) 4α,7 α aromadendranediol. reaction conditions. Thus, reaction of dienyne 79 with catalyst The formal syntheses of echinopines A and B ( 85 and 86 , 40 80 (neat) leads, via carbenoid 81 , to an intramolecular transfer Scheme 15) by Chen and co workers highlights the potential of palladium catalyzed cycloisomerization 41 to construct dienes that are suitable for subsequent Diels Alder cycloadditions. [LAu] R [LAu] Treatment of the acyclic dienyne 87 with palladium(II) acetate / R cat. Au(I), triphenylphosphine in toluene at 80 °C leads to the formation of OH O CH Cl , rt OH O 2 2 diene 88 , which undergoes in situ cycloaddition with the i-Pr i-Pr pendent nitroalkene to form tricyclic product 89 in 73% yield – H an impressive increase in molecular complexity via a highly 74a R = H ; Au(I) = AuCl (10 mol%) 76a ,b 74b R = OTES ; Au(I) = [i-PrAuNCPh]SbF6 (3 mol%) atom economical process. The mechanism of this cycloisomerization remains somewhat unclear; one possibility 41 [AuL] R R [AuL] is the initial generation of a palladium(II) hydride species, which mediates the cyclization by alkyne hydropalladation O i-Pr (90 ), then migratory insertion of the proximal alkene (91 ), and O H finally β hydride elimination to deliver the 1,3 diene product. H OH i-Pr The 7:3 mixture of epimers at the C2 position is HO 77a ,b 75a,b O inconsequential, as this oxygen substituent is destined for conversion to an exocyclic alkene in the natural products. O Ph [AuL] 42 R i-Pr R i-Pr H i-Pr Carbopalladation cascades represent an enabling and readily implemented method to achieve polycyclizations. Two O O O examples that epitomize the level of synthetic challenge that
H OH H OH H OH can be conquered with this chemistry are shown in Scheme 16. 78a 20 min, 48 % 73 : (–)-englerin B The first, a synthesis of linoexpin ( 92 , Scheme 16a) reported by 43 78b 5 h, 58 % the Tietze group, involves domino cyclization of an aryl Scheme 13. Gold-catalyzed cascades towards (–)-englerin B (series a: Ma and co- bromide 93 onto an alkyne, with capture of intermediate workers; series b: Echavarren and co-workers). alkenylpalladium species 94 by an appended allylsilane, which
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two carbopalladations leads to intermediate trienylpalladium TBSO NO 2 TBSO NO 2 complex 98 ; 6π electrocyclization / β hydride elimination, or 2 H H alkene electrophilic palladation / reductive elimination, are [Pd II ]–H possible mechanisms that could be envisaged to complete the [Pd II ] cyclization of 98 to pentacycle 99 . This product was advanced Pd(OAc) 2 (10 mol%), to rubriflordilactone A in a further 6 steps. PPh 3 (20 mol%) 87 toluene, 80°C H 90 Metathesis reactions remain a productive source of highly (C2 epimers, 7:3) atom efficient cascade polycyclizations. In this context, Prunet and co workers have achieved an enantioselective synthesis of TBSO TBSO NO 2 the ABC tricyclic core of Taxol via a cascade ene yne ene H H RCM reaction (Scheme 17a).45 This application is particularly [Pd II ] notable due to the inherent ring strain and complexity of the
NO 2 Taxol system, which still presents one of the most imposing 88 91 challenges to synthetic chemists. Here, this challenge is 73% epitomized by the problematic formation of an ene ene RCM TBSO byproduct 100 (path a) along with the desired ene yne ene 2 H H product 101 (path b), depending on which unsaturated H H component the ruthenium carbenoid ( 102, formed on initial metathesis with the unhindered terminal alkene in 103 ) engages NO COOR 2 with. This product selectivity shows high catalyst dependence: 89 85 : R = H; echinopine A (C2 epimers, 7:3) where the Grubbs II catalyst 104 gives a high yield but 86 : R = Me; echinopine B Scheme 15. Cycloisomerization / Diels-Alder approach to echinopines A and B equimolar ratio of 100 and 101, the Zhan 1B variant 105 is (Chen and co-workers). much more selective for the desired product 101. Another impressive ruthenium catalyzed metathesis cascade gives a high yield of the pentacyclic product 95 . The allylsilane has been reported by the Li group,46 in which a divergent is crucial in controlling the positioning of the exocyclic alkene synthesis of several humulanolide natural products is realized. in 95 ; among several mechanisms that could be envisaged for These anticancer targets, exemplified by (–) asteriscunolide D this final step, this may suggest a desilylative palladation of 94 (106 , Scheme 17b), comprise a challenging 11 membered ring (perhaps proceeding via a silicon stabilized carbocation), prior core featuring an ansa butenolide unit. The highly creative to rapid reductive elimination; or alkene carbopalladation, approach employed by the Li group harnesses the ring strain of followed by an unusual formal β silyl elimination. The second a cyclobutene to control formation of these two rings. Two example depicts the cascade cyclization of a complex possible mechanisms are shown, with the catalyst having a bromoendiyne 96 , used to construct the 7,6,5 tricyclic core of choice of initiation sites at the unhindered terminal alkene in rubriflordilactone A (97 ) in a total synthesis of this natural 107 , or the strained (but electron deficient) cyclobutene. The product by the Anderson group (Scheme 16b).44 A sequence of authors propose the former pathway, with a subsequent strain
a b TMS Pd(OAc) 2 TMS O (5 mol%), O XPhos Pd(PPh 3)4 (10 mol%), H (7.5 mol%), H O II Et N, MeCN, Bu NOAc, [Pd ] 3 O 4 ο O II DME, 80 °C, 1 h O 80 C, 18 h [Pd ] MeO Br Br OH MeO SiMe 2Bn O H O OH H PCy2 TBSO H O TBSO i-Pr i-Pr H 96 98 O O 94 O 93 i-Pr XPhos 91% 76% SiMe 2Bn H H O O O O H H O O H O MeO 4 steps MeO O O O SiMe 2Bn O O O OH H H H H H O O TBSO 92 : linoxepin O 95 O 97: (+)-rubriflordilactone A 99
Scheme 16. Carbopalladation cascades in the synthesis of linoxepin ( a, Tietze and co-workers) and (+)-rubriflordilactone A ( b, Anderson and co-workers).
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a b O Grubbs- O O Hoveyda II Ru cat. (108 ) (10 mol%), (20 mol%),
toluene, toluene, or OO reflux OO OO reflux [Ru] O O O O O O [Ru] O O O 103 100 101 107 108 110 path Grubbs II (104 ): 90%, 1:1 IMes a) Zhan-1B (105 ): 90%, 2:7 Cl Ru O O O Cl Ph 104 b) [Ru] PCy3 [Ru] 105 : IMes R = SO 2NMe 2 108 : Cl a) Ru R = H or Cl H path 36 % O [Ru] O OO O R OO b) O i-Pr O O O O O 102 106 : (–)-asteriscunolide D 109 111 Scheme 17. Metathesis cascades in the synthesis of the Taxol ABC ring system ( a, Prunet and co-workers), and (–)-asteriscunolide D ( b, Li and co-workers).
release driven ring opening metathesis (ROM) reaction of the encouraged to undergo further stereoselective cyclization on
cyclobutene 108 leading to the butenolide unit 109 , with the treatment with BF 3•OEt 2, achieving an overall yield of 71% for ruthenium carbenoid transferred to the ring opened side chain. this sequence, with exceptionally high enantioselectivity (>99% This then undergoes RCM with the 1,1 -disubstituted alkene, ee ). That these interrupted cascade products were also formed affording (–) asteriscunolide D (36% yield). Alternatively, initial reaction through cyclobutene ring opening (110), and OPMB OPMB metathesis with the terminal alkene, could afford intermediate TMS (R)-115 (12.8 mol%), TMS 111 prior to a separate ring closing macrocyclization. Either [{Ir(cod)Cl}2] (3.2 mol%), way, the formation of an 11 membered macrocycle through this Zn(OTf)2 (16.0 mol%), cascade is an impressive achievement, and the value of this DCE, rt, 16 h chemistry is further enhanced through transformation of HO asteriscunolide D into several other natural products. O IrL n 114 113 A highlight in transition metal catalyzed polycyclization is P N the recent development of pseudo-biomimetic enantioselective O 73% polyene cyclizations,47 albeit applications in natural product 9:1 dr (R)-115 96% ee synthesis remain rare. The Carreira group’s realization of O iridium catalyzed asymmetric polyene cyclization is therefore 112: ( +)-asperolide C OPMB highly significant, depicted in Scheme 18a in the context of a O biosynthetic approach to the labdane diterpene (+) asperolide 48 C, 112 . Building on previous methodology in which electron OH rich arenes terminate the cationic cascade, 49 an allyl silane is H H CO 2H 116 here employed as the terminating group. Thus, generation of a 1. (R)-115 (16 mol%), [{Ir(cod)Cl} ] (4 mol%), chiral π allyl iridium complex 113 from allylic acetate 114 OMe 2 Zn(OTf)2 (20 mol%), DCE, rt, 16 h ο initiates a cascade of stereoselective cyclizations before final OMe 2. BF3•OEt 2, CH 2Cl 2, 0 C, 1 h loss of this TMS group, forming the trans decalin 116 with 71%, 99% ee OMe excellent stereocontrol (96% ee, 9:1 dr ). This tricyclic scaffold OMe OMe was taken on to (+) asperolide C ( 112) in a further ten steps. 117 This chemistry has significant potential as a general method HO OMe for the synthesis of terpene natural products, as recognized by the Li group in an impressive synthesis of mycoleptodiscin A, 50 where three rings are formed in a single step (Scheme 18b). 118 49 Under the cyclization conditions, polyene 117 gave the Scheme 18 . Enantioselective iridium-catalyzed polyene cyclizations in the product 118 , albeit in low yield (21%). However, side products synthesis of (+)-asperolide C ( a, Carreira and co-workers) and mycoleptodiscin A (b, Li and co-workers). arising from premature termination of the cascade could be
This journal is © The Royal Society of Chemistry 2012 J. Name ., 2012, 00 , 1-3 | 9 Chemical Society Reviews Page 10 of 13 Journal Name ARTICLE in high enantiopurity implies, as proposed by Carreira, 49 that N N the catalyst exerts stereocontrol over the first cyclization step Me H only; the stereochemistry locked into the first formed ring then H acts to direct the subsequent cascade with exquisite control. H N H O N CO Me H 2 H Organocatalytic cascades O 119: (–)-strychnine 120 : (–)-akuammicine Efficiency in Nature is often enhanced by the formation of Me O (20 mol%) multiple natural products from a common biosynthetic N NHBoc Boc O intermediate. This is also a tantalizing goal in chemical 1-Nap N synthesis, and as such it is perhaps surprising that asymmetric t-Bu N H •Br 3CCO 2H organocatalysis has yet to be widely exploited in this SeMe diversifying context. Nonetheless, this is an ideal embraced in O N N the MacMillan group's 'collective' total synthesis of six indole PMB PMB 121 toluene, –40 °C→rt 126 alkaloids, including strychnine (119, Scheme 19) and 82%, 97% ee 51 akuammicine (120 ). All are accessed from a single form of NHBoc advanced intermediate, prepared with high enantio and Boc X diastereoselectivity via an organocascade polycyclization. N SeMe This cascade begins with an endo selective Diels Alder N t-Bu reaction between 2 (vinyl 1 selenomethyl)tryptamine 121 and N PMB propynal, with enantioselectivity deriving from orientation of N N 1-Nap 125 Me PMB the alkyne of the imidazolium ion (122) away from the bulky 122 O tert-butyl group, and an enforced approach of the selenyl diene endo [4+2] X = NR2 or OH to the top face as illustrated (where the naphthyl group blocks BocHN Boc the lower face of the reacting alkyne). The choice of a selenyl NR 2 NH X substituent is key in enabling its subsequent β elimination from SeMe 123 , affording iminium ion 124. The pendent sidechain carbamate nitrogen atom then performs a 5 exo trig cyclization N N 123 124 to form intermediate 125 , before or after hydrolytic recycling of PMB PMB the catalyst. 126 was transformed into akuammicine in a further Scheme 19. Collective total synthesis of Strychnos alkaloids using an six steps, and into strychnine in a further eight steps; with a organocatalytic cascade (MacMillan and co-workers). total count of twelve steps and an overall yield of 6.4%, this is the shortest enantioselective route strychnine completed to date: single electron transfer (SET) oxidation of the monomer a level of efficiency that is possible solely through the use of hymenidin (128 ) leads to radical cation 129, which reacts with the cascade strategy. Simple variation of the nitrogen protecting another molecule of hymenidin 128 . The subsequently formed group enabled the synthesis of four other indole alkaloids. radical has a choice of positions to effect ring closure (thus leading to different natural products); in the case of ageliferin it Radical cascades is a 6 membered ring that forms, giving the natural product after further SET and tautomerization. Recent applications of radical chemistry in polycyclizations An oxidative radical cyclization was designed by the Chen have seen use of classical methods (e.g. manganese(III) acetate) group to mimic this biosynthetic dimerization (Scheme 20b). and emerging technologies (e.g. photoredox catalysis) to Manganese(III) acetate promoted oxidation of β ketoester 130 mediate radical pathways. Both have been elegantly gives radical cation 131 , which undergoes a 5 exo trig demonstrated in the extensive work of the Chen group on the cyclization onto the pendent olefin to give radical 132 . This in synthesis of the pyrrole imidazole alkaloids ageliferin, sceptrin turn then engages in a 6 endo-trig cyclization onto the and massadine. Whilst only two new rings are produced in the imidazole ring, a cyclization that is neatly promoted over the course of this cascade process, these groundbreaking examples competing 5 exo process by the driving force of captodative pave the way for more ambitious applications. As in the stabilization of the resultant radical. Further SET oxidation and incarvitdone / incarvilleatone natural products mentioned deprotonation affords product 133 , which was taken on to earlier in this review, these sponge metabolites derive from ageliferin, bromoageliferin, and dibromoageliferin.53 dimerization of simpler natural products, in this instance The Chen group has also accomplished enantioselective through formal [4+2], [3+2], and [2+2] cycloadditions of syntheses of the sceptrin natural products, again using oroidin and its derivatives. 52 This relationship makes a common biomimetic oxidative cyclizations. 50 In this case, the key synthetic approach to these compounds an attractive prospect. cascade cyclization of substrate 134 was attempted with several The biosynthesis of ageliferin ( 127 , Scheme 20a) provides an single electron oxidants, but success was only met via a informative backdrop to this synthetic chemistry: enzymatic photoredox strategy involving reversible single electron transfer
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(see also Scheme 6), in which opposite pseudo-enantiomeric a H H H HN H series of natural products are produced by monomer homo / HN N HN N HN N N NH heterodimerization, with the oxidative dimerization processes NH HN HN HN HN N being mediated by discrete enzymes, rather than a common H biosynthetic pathway as had been assumed prior to this work. SET Samarium(II) iodide chemistry has experienced a HN O HN HN HN HN renaissance in recent years, not least through the realization of O O O some ambitious, complexity inducing transformations mediated O HN by this reagent. 54 A recent example that highlights the utility of HN NH NH NH Br this chemistry is found in a synthesis of maoecrystal Z (138 , Br Br Br Br Scheme 21) by the Reisman group.55 Containing six contiguous 128 : hymenidin 129 128 127 : ageliferin stereocentres within a congested tetracyclic ring system, this molecule clearly represents a significant synthetic challenge. b N3 N 3 The key radical cascade was deployed at a relatively late N O N O stage of the synthesis. Model studies had revealed the beneficial BOM N NBoc BOM N NBoc effect of performing the SmI 2 mediated reductive cyclization in Mn(OAc) 3, O AcOH, 60 °C HO the presence of a lithium halide and t-BuOH, where the lithium BocHN BocHN salt is believed to increase the reducing power of the samarium O O 130 O O 131 diiodide, while the alcohol acts as a proton source. Application – H + of these conditions to dialdehyde 139 initially leads to ketyl N3 N3 radical anion generation at the least sterically hindered O O N N H – + aldehyde ( 140 ). This is followed by cyclization to 141 , with a N – e , – H N BOM N BOM N further single electron reduction forming enolate 142 , which Boc Boc H 30% H engages in intramolecular aldol cyclization onto the remaining O dr 2.5-3:1 O aldehyde to give tetracycle 143 in a remarkable 54% yield as a BocHN O BocHN O O 133 O 132 single diastereomer. The high stereoselectivity of the radical cyclization was rationalised by orientation of the aldehyde such c that destabilizing steric interactions with the proximal N3 1. PPh Ph 3P 3 N N 2. h ν (fluoresecent N dr = 1.8:1 cyclohexane ring are minimized; chelation of the samarium to strip light), BOM N the lactone carbonyl may also be of importance. The Ir(ppy) 3 (3 mol%) N H BOM H H OTIPS stereoselectivity of the final aldol cyclization is likely controlled by a pseudo-equatorial positioning of the aldehyde. O O H 143 was taken on to complete the first total synthesis of (–) O O OTIPS 134 H 135 maoecrystal Z, with just 12 steps in the longest linear sequence.
TiCl , 43% H H 4 N N HS(CH2)3SH (3 steps) HN NH H H H Ph 3P N OTIPS H N N SmI 2, LiBr H H N H O O Br Br N O H O OH t- BuOH Sm III BOM H THF, –78 °C O O H O O NH HN S 139 140 N N H H OH S O O 137 : ent -Sceptrin 136 H H H H Scheme 20, Synthesis of pyrrole-imidazole natural products by radical cascades SmI 2 (Chen and co-workers). O O Sm III O O Sm III H O O H O O between the substrate (the amino imidazole group) and Ir(ppy) 3 142 141 catalyst (Scheme 20c). This imaginative chemistry gave 54% cyclization product 135 (1.8:1 dr ), with the sceptrin core 136 H H revealed through exposure of 135 to titanium tetrachloride and 1,3 propanedithiol. This cyclobutane was taken on to complete HO HO H the synthesis of ent sceptrin (137); these enantioselective OH OAc O O O syntheses in fact led to a call for a reassignment of the absolute O O stereochemistry of both sceptrin and ageliferin, as each led to 143 138 : (–)-maoecrystal Z the unanticipated antipode of the natural products. This has Scheme 21. SmI 2-mediated cascade cyclization in the synthesis of (–)-maoecrystal Z (Reisman and co-workers). raised the interesting concept of ‘enantiodivergent biosynthesis’
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Key learning points:
1. Cascade (domino) polycyclizations are among the most efficient, ambitious, and elegant tools for the synthesis of polycyclic natural products.
2. A variety of reaction types (pericyclic, heteroatom-mediated, cationic, metal-catalyzed, organocatalytic and radical) can be employed in cascade polycyclizations.
3. Cascade reactions can lead to new biosynthetic hypotheses, highlighted in this review through homo- and heterochiral dimerizations.
4. Important advances have been made in enantioselective polyene cyclizations promoted by transition metal catalysts and halonium ions.
5. Transition metal-catalyzed cascades offer efficient and unique methods for bond formation to prepare polycyclic natural products.