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 Page 1 of 13 Chemical Society Reviews 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. TIPSO HO A final 'pericyclic' example is found in Leighton and co- O 21 O 16 : cyclocitrinol 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 This journal is © The Royal Society of Chemistry 2012 J. Name ., 2012, 00 , 1-3 | 2 Page 3 of 13 Chemical Society Reviews Journal Name ARTICLE 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 31 : (±)-incarvilleatone (23%) 32 64% yield of 21 is obtained after hydrolysis and esterification. Scheme 6. Homochiral and heterochiral oxa-Michael initiated cascades to (±)- Heteroatom-mediated cascades incarviditone and (±)-incarvilleatone (Lawrence and co-workers).