Organic & Biomolecular Chemistry Recent applications in natural product synthesis of dihydro - furan and -pyran formation by ring-closing alkene metathesis Journal: Organic & Biomolecular Chemistry Manuscript ID OB-REV-03-2016-000593.R1 Article Type: Review Article Date Submitted by the Author: 12-Apr-2016 Complete List of Authors: Hodgson, David; Oxford University, Jacques, Reece; Oxford University Pal, Ritashree; Oxford University Parker, Nicholas; Oxford University Sear, Claire; Oxford University Smith, Peter; Oxford University Ribaucourt, Aubert; Oxford University Page 1 of 18 OrganicPlease & Biomoleculardo not adjust margins Chemistry Journal Name Review Recent applications in natural product synthesis of dihydro-furan and -pyran formation by ring-closing alkene metathesis a a a a a Received 00th January 20xx, Reece Jacques, † Ritashree Pal, † Nicholas A. Parker, † Claire E. Sear, † Peter W. Smith, † Aubert a a Accepted 00th January 20xx Ribaucourt and David M. Hodgson * DOI: 10.1039/x0xx00000x In the last two decades, alkene metathesis has risen in prominence to become a significant synthetic strategy for alkene formation. Many total syntheses of natural products have used this transformation. We review the use, from www.rsc.org/ 2003 to 2015, of ring-closing alkene metathesis (RCM) for the generation of dihydro-furans or -pyrans in natural product synthesis. The strategies used to assemble the RCM precursors and the subsequent use of the newly formed unsaturation will also be highlighted and placed in context. (Scheme 1, X = O, m = 0,1; n = 1,2,3). A critical overview is given. Introduction The aim is to provide the reader with an appreciation of the various ways that such RCM chemistry has been, and could be, employed as The potential of metal-complex catalysed alkene metathesis as a key strategic element to facilitate target synthesis. RCM substrate useful synthetic methodology began to be widely assimilated by assembly and post-RCM manipulations are also analysed. Direct organic chemists in the early 1990s. This followed the development formations of furanones and pyranones by RCM of unsaturated and demonstrated utility of easy to handle and functional group- 1,2 esters have recently been nicely reviewed in the context of natural tolerant Ru catalysts. The chemistry has proved especially product syntheses, 4 and are not further discussed here. In the convenient in carbo- and hetero-cyclic ring synthesis (Scheme 1). 5- current review, examples are grouped according to RCM product And 6-membered oxacycles constitute important heterocyclic 3 ring size and double bond position (2,5-DHF, 2,3-DHF, 3,6-DHP, 3,4- motifs, found in a variety of bioactive natural products. A DHP sections); within the sections, similarly substituted systems, significant number of total (or fragment) syntheses of such and the routes to them, are compared. Coverage is from mid-2003 5 oxacycle-containing natural products have been reported using to end-2015. 6-8 ring-closing alkene metathesis (RCM) as a key step, typically using Grubbs 1 st or 2 nd generation catalysts ( GI , GII ), or Hoveyda-Grubbs II catalyst (HGII ). 2,5-Dihydrofurans For 2-substituted 2,5-DHFs, RCM is a straightforward strategic m Ru cat m X X disconnection, due to the ease of RCM substrate construction, R typically by aldehyde C-vinylation −O-allylation. For example, n n R the free-radical scavenger ( ─) -gloeosporiol (2) was accessed through RCM of an ether 1 available by O-allylation of the MesN NMes MesN NMes corresponding enzymatically-resolved benzylic alcohol PCy Cl 3 Cl Cl (Scheme 2). 9 Subsequent diastereoselective dihydroxylation Ru Ru Ru and desilylation completed the synthesis. Cl Ph Cl Ph Cl PCy3 PCy3 i-PrO GI GII HGII Scheme 1 Ring-closing alkene metathesis (RCM) and Ru catalysts commonly used. This review focuses on total, formal and fragment syntheses of natural products that possess 5- or 6-membered oxacycles, where a dihydrofuran (DHF) or dihydropyran (DHP) is formed by RCM This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1-3 | 1 Please do not adjust margins OrganicPlease & Biomoleculardo not adjust margins Chemistry Page 2 of 18 Review Journal Name 12 O principle, a chiral RCM catalyst could induce stereoselectivity O GI (10 mol%) CH 2Cl 2 (10 mM) in the RCM step. reflux, 2 h TBSO 98% TBSO 1. CeCl 3 OTBS OTBS O O O 1 O O MgBr O OsO , Me NO 4 3 2. NaH, HMPA Br O O EtO2C 7 OH O OH O I2, MeOH OH OH HO TBSO cat. GI PhMe OH OTBS 65 °C, 24 h 2 95% 9:1 dr (major diastereomer shown) O O H H H Scheme 2 Synthesis of (─)-gloeosporiol (2). H O H 1,2-Reduction of an enone, then O-allylation delivers an MeO2C O O O alternative entry to metathesis substrates that lead to 2- 10 9 8 substituted 2,5-DHFs. This strategy formed part of a stereochemically flexible approach to bis-THF containing Scheme 4 Synthesis of the core of hippolachnin A (10 ). acetogenins (Scheme 3), 10 where the enones (eg, 4) were derived from regio- and stereo-selective [5+2] cycloaddition of With cyclic ketones, C-vinylation −O-allylation followed by RCM in situ generated 3-oxidopyrylium (3) with alkene leads to spiro-fused DHFs. In a model study, the tricyclic dipolarophiles. In these cases, the 2-substituted 2,5-DHF 6 is framework 11 of the cytotoxic yaoshanenolides 12 was 13,14 produced through strain relief-driven ring rearrangement completed in this fashion (Scheme 5). metathesis (RRM), and is carried out in the presence of 1,4- OH benzoquinone under an ethylene atmosphere. The quinone Me(CH ) HGII (5 mol%) 2 n O alleviates competitive allyl ether to 1-propenyl ether CH Cl (38 mM) O 2 2 O isomerisation, likely catalysed by Ru hydrides generated in the rt, 5 h O CH OMe reaction. The ethylene promotes catalyst release following ring CH 2OMe 93% 2 rearrangement. Mitsunobu inversion at the allylic alcohol 5 Et Et stage broadens the methodology to encompass 11 12 i-Pr stereochemically different acetogenin targets. n = 10 yaoshaneolide A n = 12 yaoshaneolide B O HO O O NaBH 4 Scheme 5 Model studies towards yaoshanenolides A and B. 130 °C CeCl Ph O 3 O O OAc O The strategy of C-vinylation −O-allylation followed by RCM has 3 4 5 Ph Ph been applied in several instances to cyclic ketones bearing α- 15,16 NaH, Br hydroxymethyl functionality. In such cases, subsequent HGII (10 mol%) allylic oxidation of the spiro-fused DHF 13 generates the 1,4-benzoquinone (20 mol%) corresponding furanone, which undergoes oxa-Michael O ethylene (1 atm) O CH Cl (30 mM) addition; this provides a rapid entry to tricyclic systems O 2 2 O rt, 3 h containing the furo[3,2-b]furanone motif 14 (Scheme 6). 17 The 50% ABC ring systems 15 of the nortriterpenoid anti-HIV agents 6 Ph Ph micrandilactone A (16 ) and lacnifodilactone G were prepared 18 Scheme 3 Ring rearrangement metathesis (RRM) towards from D-mannitol using this strategy (Scheme 7). acetogenins. For 2,2-disubstituted DHFs, ketone C-vinylation −O-allylation provides a convenient approach to RCM substrates. For example, the tricyclic core 9 of hippolachnin A (10 ) was recently synthesised from a D-mannitol-derived RCM substrate 7 made in this way (Scheme 4). 11 Metathesis using GI likely initiated at the least hindered terminal olefin of the tetraene 7, with RCM occurring non-stereoselectively at the formally diastereotopic vinyl groups. Following acetonide manipulation, only one of the two diastereomeric 2,5-DHFs 8 subsequently underwent intramolecular [2+2] photocycloaddition. In 2 | J. Name ., 2012, 00 , 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Page 3 of 18 OrganicPlease & Biomoleculardo not adjust margins Chemistry Journal Name ARTICLE OH O O OTBDPS 1. NaBH 4, CeCl 3 OTBDPS 1. O MgBr 2. NaH, Bu 4NI R Br R O O 2. NaH, Br O O O O H 3. Et Al-TMP H H O 2 O TBDMSO GI (5 mol%) 17 TBDMSO 18 H H CH 2Cl 2 reflux, 12 h R = Me or CO 2Me GII (15 mol%) 91% H 1,4-benzoquinone (25 mol%) CH 2Cl 2 (17 mM) O O OTBDPS R2 R2 reflux, 50 min OH 1. PDC, t-BuOOH O O O O 1 2. TBAF R R O O O O O 14 O 13 H H H TBDMSO 19 Scheme 6 Synthesis of embedded furo[3,2-b]furanone in a H H trioxatriquinane. (−)-marginatone: R1 = Me, R2 = =O R = Me (90%), 1 2 CO 2Me (88%) (−)-20-acetoxymarginatone: R = CH 2OAc, R = =O O (−)-marginatafuran: R1 = CO Me, R2 = H 2 H CO 2Et O O Scheme 8 Synthesis of isospongian diterpenoids. H OBn O O A synthesis of the furan cembranolide (─)-(Z)-deoxypukalide 1. MgBr (24 ) involved generation of a transient 2,3,5-trisubstituted DHF 20 2. NaH, Bu 4NI by RCM (Scheme 9). Selective ozonolysis of the trisubstituted Br alkene in the TIPS ether of ( S)-perillyl alcohol 20 , followed by aldehyde selective addition of a vinyl alane from methyl O O GI (5 mol%) propiolate gave an allylic alcohol 21 (1:1 dr, mixture CH 2Cl 2 (10 mM) rt, 3 h inconsequential). Acid-catalysed acetal exchange with acrolein O O diethyl acetal gave the RCM precursor 22 . RCM, initiating at H 94% H OBn OBn the less-substituted terminal alkene, gave an α-ethoxy- O O substituted DHF, which underwent acid-catalysed elimination O of EtOH/aromatisation; the resulting 2,3-disubstituted furan O O 23 was taken forward to the target macrocycle 24 .