Recent Applications in Natural Product Synthesis of Dihydro- Furan and -Pyran Formation by Ring-Closing Alkene Metathesis

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

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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 iPrO 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

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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 iPr 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 1,4benzoquinone (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

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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 AlTMP 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 1,4benzoquinone (25 mol%) CH 2Cl 2 (17 mM) O O OTBDPS R2 R2 reflux, 50 min OH 1. PDC, tBuOOH O O O O 1 2. TBAF R R O O O O 14 O 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%) (−)20acetoxymarginatone: R = CH 2OAc, R = =O O 1 2 (−)marginatafuran: R = CO 2Me, R = H 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 . OH OH O H A O H OH OTIPS H H O 1. O3, then Me 2S O B C MeO2C O O O H 2. CO 2Me, O H 21 H OBn H OH DIBALH O R 15 OEt micrandilactone A (16 ) 20 , PPTS R = Me, CH 2OTBDMS TIPSO OEt OEt Scheme 7 Synthesis of the ABC ring systems of O OTIPS micrandilactone A and lacnifodilactone G. GII (8 mol%) CH 2Cl 2 (0.1 mM) reflux, 16 h 22 Direct access to 2,3-disubstituted DHFs by RCM requires a 2,2- then PPTS CO 2Me O disubstituted-1-alkene in the substrate. Syntheses of the 85% (2 steps) isospongian diterpenoids (─)-marginatafuran, (─)-marginatone CO 2Me and (─)-20-acetoxymarginatone used such an approach O OTIPS (Scheme 8). 19 Carvone-derived α,β-epoxy ketones 17 underwent stereoselective reduction, then O-allylation and O MeO C regioselective epoxide to allylic alcohol isomerisation using 2 23 O diethyl aluminium-tetramethylpiperidide (TMP), to give the RCM precursors 18 . Homodimerisation and allyloxy to enol O ether isomerisation in the RCM step were supressed by 24 O dilution and addition of 1,4-benzoquinone. Subsequent oxidation of the fused DHF 19 with DDQ gave the furan motif Scheme 9 Synthesis of (─)-(Z)-deoxypukalide (24 ). present in the natural products. A synthesis of the NBoc-protected α-amino acid antibiotic (+)- furanomycin 28 (Scheme 10), 21 illustrates that the aldehyde C- vinylation −O-allylation RCM strategy can be extended to 2,5-

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Review Journal Name disubstituted DHFs 27 . The RCM substrate 26 synthesis EtOOC OH OH involved syn -selective alkynylation of serine-derived Garner’s aldehyde 25 and non-stereoselective O-allylation. After RCM, EtOOC OH OPMB hydrolysis and oxidation gave NBoc-furanomycin 28 , along 32 34 with its methyl epimer. BnO OH OPMB O NBoc NBoc TMS NBoc 33 35 BuLi, ZnBr 2 O O O Cu(OTf)2 TMS 25 O OH OH cat. GII CH Cl , 18 h Cl Bu NBr, 2 2 4 BnO BnO Ag 2O O OPMB O OPMB H H 79% H H OR 36 OBn 37 GII (7 mol%) NaH R = H benzene NHBoc NBoc NBoc R = Bn reflux, 36 h BnBr OH O O HO 2C BnO 66% O 28 O 27 O 26 O 19 H H OBn 38 O O Scheme 10 C-vinylation −O-allylation RCM strategy to NBoc- furanomycin 28 . OH OH 19 An alternative approach to a similar RCM substrate for H O OH H 34 furanomycin synthesis involved Ireland-Claisen rearrangement H H O 1 O (Scheme 11). 22 Base-catalysed conjugate addition of ( S)-but-3- en-2-ol (29 ) to methyl propiolate led to an allylic E-enol ester. OH O 39 DIBALH reduction gave the corresponding alcohol, which coupled with NBoc 2-protected glycine to give the Scheme 12 Stereocontrolled synthesis of C19 −C34 segment of rearrangement substrate 30 . [3,3] Sigmatropic rearrangement amphidinolide C. of the Z-silyl ketene acetal 31 proceeded with complete relative stereocontrol for the two newly created stereocentres A synthesis of the anticancer agent (─)-mucocin (43 ) involved and modest (72:28) stereocontrol relative to the pre-existing construction of a 2,5-disubstituted DHF 42 by RCM, where stereocentre. stereochemistry is introduced onto an acyclic ether 41 prior to RCM (Scheme 13). 25,26 The first DHF stereocentre was O O generated via kinetic resolution using SAE. Subsequent O- LHDMS (Boc) 2N O HO TMSCl H O alkylation with bromoacetic acid and introduction of Evans’ (Boc) 2N OTMS auxiliary gave an N-glycolyl oxazolidinone 40 . A Lewis acid- O Me catalysed syn -aldol reaction with acrolein generated the 29 30 31 second (α’-) stereocentre, as well as the adjacent hydroxyl then CH N 2 2 stereocentre (destined to be exocyclic). Auxiliary removal and N(Boc) N(Boc) homologation provided the RCM substrate 41 , with an 2 GI (5 mol%) 2 CH Cl unsaturated tether that was found to be crucial in providing 2 2 MeO C MeO2C 20 °C, 40 h 2 RCM selectivity. RCM without the tether led to a mixture of O O 85% desired DHF 42 and 2,5-DHP, due to the similar affinity of either terminal alkene for the catalyst. With the engineered Scheme 11 Ireland-Claisen RCM strategy to furanomycin. tether, relay RCM occurs: the catalyst first reacts with the less- hindered, electronically activated terminal alkene, then A synthesis of a 2,5-disubstituted DHF 37 , where the α-,α’- liberates a molecule of 2,5-DHF, resulting in the stereochemistry in the acyclic ether RCM precursor 36 is metallocarbene at the desired position for selective 2,5-DHF assembled with high stereocontrol, is found in studies to the formation. Three-fragment assembly of the mucocin skeleton C19 −C34 segment 38 of the cytotoxic marine natural product was then achieved via cross-metathesis to install the amphidinolide C (39 ) (Scheme 12). 23,24 One of the tetrahydropyran section, followed by Sonagashira coupling to stereocentres was developed from (+)-diethyl tartrate (32 ) as add the 2,5-dihydrofuranone. The tetrahydropyran portion an enantiopure allylic alcohol 33 , while the other was was also made by RCM, and is discussed later in this review generated via Sharpless asymmetric epoxidation (SAE, 92:8 er) (Scheme 32). Completion of the synthesis was achieved by on the mono PMB ether of cis -2-butene-1,4-diol 34 ; the latter mild hydrogenation of the connecting unsaturated double was inverted at the allylic position via Lewis acid-mediated bond using diimide. opening of epoxide 35 by the allylic alcohol 33 .

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O TIPS O PhSe TIPS O SAE N O O OTBDPS

3 O HO Bn 40 O OTBDPS X O X = O 44 OTBDPS TiCl4, iPr 2NEt TBDPSO Cp 2TiMe 2 O X = CH 2 45 O TIPS OR PhSeCl then LiAlH N O O 4 O Bn TiLn α' O N Bn O H O O 4:1 dr O OTBDPS OTBDPS OH (major diastereomer shown) α α' 46 R

O PhSe OTBDPS TIPS TIPS GI (5 mol%) 3:1 dr (R = H) GII (10 mol%) CH 2Cl 2 (20 mM) (major diastereomer shown) benzene (10 mM) rt, 18 h 80 °C, 5 min O O H H H H 41 then PTSA 87% 42 OTBDPS OTES MeOH OH O H H OTBDPS O

OH OH 47 69% 48 22% H H O C H O 10 21 O H H O Scheme 14 Synthesis of an eleutherobin analogue. OH 43 HO RCM was used to make a DHF 52 present in the smaller Scheme 13 Synthesis of ( ─) -mucocin (43 ). bridged framework of bruguierol A (53 ) (Scheme 15). 28 O- RCM has been used to generate bridged/2,5-substituted DHFs Ethylation and homologation of 3-hydroxybenzaldehyde was from cyclic ethers bearing vinyl groups at the α- and α’- followed by Friedel-Crafts acylation to give a ketoaldehyde 49 . positions. A simplified analogue 47 of the anti-mitotic Double vinylation and acid-catalysed dehydrative cyclisation diterpenoid eleutherobin was constructed in this fashion gave an inseparable 1:1 mixture of diastereomeric divinyl 27 (Scheme 14). Claisen rearrangement of a 2-deoxy-D-ribose ethers 50 and 51 , but only the cis -divinyl system 50 underwent derivative gave a 9-membered lactone 44 . 3:1 dr At the α-,α’- reaction with GII , to give the bridged DHF 52 . Hydrogenation positions was generated through chloroselenation─reductive of the alkene, followed by de-ethylation gave (±)-bruguierol A dechlorination of the methylenated lactone 45 . RCM using GI (53 ). on the derived divinyl ether 46 of the major diastereomer gave O HO a mixture of the desired bridged DHF 47 (69%) and a bis- cyclopentenyl ether 48 (22%) from RRM; the more active GII BrMg OH gave more of the RRM product 48 . Formation of the latter was EtO EtO 49 H avoided by temporary epoxidation of the cis double bond in CHO H SO the 9-membered ring; deoxygenation was effected after RCM 2 4

using WCl 6 and BuLi. A related potential RCM substrate 46 (R = OMe) failed to undergo RCM, likely due to steric hindrance. O O

EtO EtO 51 50 1 : 1 cat. GII CH 2Cl 2, rt, 7 h 47%

1. Rh(PPh ) Cl, H O 3 3 2 O

HO H 2. EtSNa EtO H 53 52

Scheme 15 Synthesis of (±)-bruguierol A (53 ).

2,3-Dihydrofurans The enol ether character of 2,3-DHFs (and 3,4-DHPs) leads to application in spiroketal synthesis, by cyclisation of a hydroxyl- bearing tether at the 5-position. Direct access to 2,3-DHFs

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Review Journal Name through RCM requires an acyclic enol ether of a homoallylic required substitution pattern. For example, 2-methyl-3,6-DHP alcohol as the precursor. A convergent strategy involving this (63 ), prepared by RCM from allylated (R)-4-penten-2-ol (62 ), approach was described to the C15–C38 fragment 60 of the provided divergent access to ophiocerins A-C (Scheme 17). 30 protein phosphatase (PP1 and PP2A) inhibitor okadaic acid (61 ) OH (Scheme 16). 29 Regioselective hydroboration of a terminal HO KH, 18crown6 alkene 54 , followed by immediate Suzuki coupling with an unsaturated ester-derived enol phosphate 55 gave an enol Br O HO O ether 56 that was used directly in RCM; potential ophiocerin C 62 intramolecular Heck-type chemistry of the enol phosphate was cat. GI not a complicating issue. DDQ-induced PMB deprotection on CH 2Cl 2 the resulting acid-sensitive crude DHF 57 led to spontaneous OH OH spirocyclisation, giving a ~3:1 diastereomeric mixture of HO HO OsO 4, NMO + spiroketals 58 and 59 . The undesired minor diastereomer 59 O could be equilibrated under acidic conditions to provide more O O 63 of desired spiroketal 58 (71%). DHF 57 was originally planned ophiocerin A 27% over 3 steps 35% over 3 steps MCPBA to come from Suzuki coupling of a lactone-derived enol phosphate, avoiding an RCM step; however, the cyclic enol OH O O phosphate was found to readily hydrolyse back to the lactone. HO NaOH + OTIPS OTIPS O O O PMBO OBn 9BBN PMBO OBn ophiocerin B, 30% over 4 steps O SPh B O SPh H 54 H Scheme 17 Synthesis of ophiocerins A-C.

OBn OBn O O LHMDS O O O Anti C-allylation of D-mannitol-derived isopropylidene (PhO)2P(O)Cl P OPh cat. Pd(PPh 3)4 glyceraldehyde 64 , followed by O-allylation, isopropylidene OPh Cs 2CO 3 55 cleavage and RCM, gave protected 2-hydroxymethyl-3,6-DHPs (eg, 65 ) that have been used in pyrano-fused pyrazine OTIPS OTIPS 31 31 b PMBO OBn PMBO OBn synthesis (eg, Scheme 18 ). The corresponding epoxide of GII (15 mol%) OBn the RCM product underwent ring-opening with azide, then PhMe (5 mM) O BnO O O SPh O SPh oxidation to give an azido ketone 66 . Reduction of the azide 66 H 70 °C, 1 h H 57 56 to the amine led to dehydrative dimerisation −aromatisation in DDQ the presence of air, to give ( S,S )-palythazine (67 ). OTIPS OTIPS H H O OH O OBn O OBn BnO BnO + Zn O O H O SPh O SPh O Br O H 58 H 59 O O 35% over 3 steps 12% over 3 steps 64 PPTS

OTIPS H GI (2 mol%) O O O TBDPSO 15 O O OBn CH2Cl 2 (0.2 M) OBn O O 65 rt, 10 h H H 1. MCPBA 88% TIPSO 60 2. NaN 3 3. DMP OH 1. H , Pd/C H N3 2 N HO 2C O O O HCl HO O O O O OBn O OH OH 1515 2. Et 3N, air OH O O 3838 O N 61 H H 66 67 OH Scheme 16 RCM −spiroketalisation approach to okadaic acid (61 ). Scheme 18 Synthesis of ( S,S)-palythazine (67 ).

RCM of the allyl alcohol - butadiene monoepoxide addition 3,6-Dihydro-2H-Pyrans product 68 , to give 3-hydroxy-3,6-DHP (69 ), was involved in the preferred route to the corresponding pyranone 70 that was used Between 2003 and 2015, there were over 30 reported in a synthesis of the pyranonaphthoquinone pentalongin 71 applications of RCM generating 3,6-DHPs in natural product (Scheme 19). 32 Prior syntheses of the pyranone 70 used vinyl synthesis. Allylation of homoallylic alcohols is a popular stannane-unsaturated acid chloride Pd-catalysed coupling and approach to the RCM substrates, with a variety of methods subsequent RCM (17%), or a Hg(II)-mediated ring-closure from being used to access the homoallylic alcohols, depending on the an alkyne (21%).

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O OH OH O Scheme 21 Synthesis of L-(+)-noviose (79 ) from benzyl glyoxylate. GII (1 mol%)

CH 2Cl 2, rt, 24 h PCC The second synthesis of L-(+)-noviose (79 ) uses O O 73% O O diastereoselective (90:10 dr) vinylation of a lactic acid-derived 68 69 70 71 aldehyde to introduce the methoxy-bearing stereocentre O (Scheme 22). 35 RCM with GI is followed by addition of t- Scheme 19 Synthesis of pentalongin. BuOOH and conversion to a pyranone 80 in a one-pot procedure; the hydroperoxide converts GI into a catalyst for A 2,3-disubstituted -3,6-DHP 74 was made by RCM in a synthesis allylic oxidation. Subsequent MOM deprotection and of the styryl-lactone (+)-howiionol (75 ) (Scheme 20). 33 methylation intersects with the earlier synthesis. Deacetalisation of a glucose derivative 72 gave a hemiacetal

that underwent olefination with a stabilised Wittig reagent, to OH 1. TBSCl OTBS 1. MOMBr OH give the RCM substrate 73 . Following RCM, diol protection 2. DIBALH 2. TBAF CO Et 3. DMP using 2,2-dimethoxypropane, then PDC-induced allylic 2 3. ClMg HO 4. MeMgCl MOMO oxidation and finally acetonide removal gave (+)-howiionol (75 ). NaH Br Ph Ph O O GI (5 mol%) O benzene (1 M), 40 oC, 2 h then O O O 1. aq. AcOH O O O MOMO 80 tBuOOH (5.5 M in decane) MOMO 40 oC, 3 h 2. CO 2Et 1. TFA Ph O O Ph 51% 2. Ag 2O, MeI Ph 3P 72 O OEt 73 OH OH O OH O O O cat. GII 1. DIBALH PhMe (13 mM) Ph Ph reflux, 12 h 2. dihydroxylation MeO OH 70% MeO 79 OH O Scheme 22 Synthesis of L-(+)-noviose (79 ) from ethyl S-lactate. O O O O O O

Ph Ph Two approaches to the microtubule-stabilising agent laulimalide OH OH OH OH (83 ) use RCM to make the 2,4-disubstituted -3,6-DHP that is 75 74 attached to the macrocyclic lactone (Schemes 23 and 24). Both Scheme 20 Synthesis of (+)-howiionol (75 ). studies apply Julia–Kocieński olefination chemistry from the same DHP-containing sulfone 82 to extend the 2-substitution, where the Two syntheses of L-(+)-noviose (79 ), the sugar component of the sulfone-stabilised anion does not cleave the DHP by β-elimination. anticancer agent novobiocin, involve formation of 2,2,3- In the first synthesis (Scheme 23), 36 access to the DHP sulfone 82 trisubstituted -3,6-DHPs by RCM (Schemes 21 and 22). In the first for aldehdye olefination begins with a Mitsunobu reaction on (R)- approach (Scheme 21), 34 key steps to the RCM substrate are glycidol using a tetrazole thiol. This was followed by terminal asymmetric Brown allylation of benzyl glyoxylate (76 ), and epoxide opening with isopropenyl copper, Pd-catalysed allylation of terminal alkene isomerisation to the 2-propenyl equivalent using the zinc alkoxide, oxidation to the sulfone 81 and RCM. In the GII (77 →78 ); a Ru-H is the likely active catalytic species, formed second approach, the DHP stereocentre is installed by aldehyde in situ from heating GII in reagent grade methanol. After RCM, methallylation under Keck conditions, followed by Williamson noviose (79 ) was obtained by allylic oxidation to the pyranone, etherification (Scheme 24). 37 The resulting diallyl ether was 1,2-redution and dihydroxylation. Compared with earlier elaborated to the DHP sulfone 82 either by performing RCM prior to carbohydrate-based syntheses, triol generation at the end tetrazole formation (as shown; GI sufficed in this case), or by PMB avoided hydroxyl group protection/deprotection manipulations. ether conversion using Mitsunobu chemistry to the same RCM sulfone substrate 81 shown in Scheme 23 . CO Bn 1. (+)(Ipc) 2B CO 2Bn CO 2Bn 2 GII (10 mol%) NaOH/ H2O2 O MeO MeO Et 3N, MeOH 762. Ag 2O, MeI 77 78

96:4 er 1. MeMgBr (2 eq) 2. NaH, allyl iodide 1. PCC GII (5 mol%) O OH 2. DIBALH O O CH 2Cl 2 (1 mM)

3. cat. OsO 4 MeO OH NMO MeO rt, 20 h MeO 87% 79 OH

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N N MgBr O N N N 1. , cat. CuI O S S N N X O N 2. OAc Ph O Li/NH 3, tBuOH Ph Et 2Zn, cat. Pd O O O X Mo 7O24 (NH4)6, H2O2 O O 84 85 N N N N GII (3 mol%) N N O O X = O O CH 2Cl 2 (0.015 M) O Ph P=CH S N rt, 3 h S N O 3 2 86 X = CH 2 O O Ph O O Ph 95% 82 81 GII (8 mol%) CH 2Cl 2, (0.02 M) O PMP rt, 14 h O PMP O 91% LHMDS O O OMOM O O O OMOM O O O OH O HO O 1313 87 O O OH exocyclic = cacospongionolide B O O 83 H H endocyclic = cacospongionolide E O 2828 Scheme 25 Syntheses of cacospongionolides B and E.

Scheme 23 Synthesis of laulimalide (83 ). A modestly diastereoselective DDQ-mediated oxidative allylation was used to make the allylic-homomoallylic ether RCM substrate 88 in a synthesis of the 2,6-cis -disubstituted tetrahydropyran core 89 OPMB OPMB of (±)-centrolobine (90 ) (Scheme 26). 39 OPMB HO O SnBu 3 NaH O Me 3SI 1. NaH, PMBCl Br Ti(iPrO)4 O BuLi 2. PPTS, MeOH H (S)BINOL HO O 3. TBSCl 98:2 er OTHP OTHP OTBS MeO GI (5 mol%) DDQ, then PhCH3 (0.01 M) CH 2=CHCH2SnBu 3 110 oC, 6 h 92% N N OPMB N O O GI (10 mol%) S N CH 2Cl 2 (0.03 M) O reflux, 3 h O O O Ph 89 OTBS 88 OTBS 82 MeO MeO 55% O 67:33 dr O O OTBDPS (+ 28% transdiastereomer) (major diastereomer shown) KHMDS O OTBDPS O OMOM O OMOM

Scheme 24 Synthesis of C13 −C28 portion of laulimalide. O 90 MeO OH The 2,5-disubstituted -3,6-DHP found in the marine sponge metabolites cacospongionolides B and E 87 has been prepared Scheme 26 Synthesis of centrolobine (90 ). by RCM (Scheme 25). 38 The unsaturated decalone portion 84 of the natural products, prepared by asymmetric Robinson A cis -2,6-disubstituted -3,6-DHP was made by RCM during annulation of 2-methylcyclohexane-1,3-dione and ethyl vinyl studies on the configuration of the antifungal goniodomin A (94 ) 40 ketone, underwent reductive conjugate addition to an enone 85 (Scheme 27). Two chiral alcohols were connected using (available from Brown’s asymmetric allylboration of 3-furfural), bromoacetic acid. The resulting glycolate ether 91 gave the RCM followed by double ketone Wittig methylenations to generate substrate 93 following Ireland–Claisen rearrangement through the RCM substrate 86 . Exposure of this triene 86 to GII led to the methyldichlorosilyl ketene acetal 92 ; use of less reactive RCM, likely initiated at the less-hindered terminal olefin, and TMSCl gave significant by-product due to [2,3] Wittig completed the carbon skeleton of the natural products. rearrangement.

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diastereoselective allylation of the enolate of an N-glycolyl oxazolidinone. O O OBn OBn HO O O O MOMO MOMO OH 91 OPMB LHMDS OPMB GII (10 mol%) MeSiCl3 O O iPr CH 2Cl 2 (5 mM) iPr OSiMeCl2 reflux, 24 h N O 89% N O CH N O O 2 2 99 100 O O O O O O 92 Me Me O HO O PMBO OAc MeO2C 93 OMe B PMBO O O 1. cat. GII , CH 2Cl 2, reflux I 2. LiAlH MeO 4 O OH MeO OH H OH OH O O Me O O O Me O O 101 HO O Me OH PMBO O OH O 81% CO Me O OH 2 O O Scheme 29 Studies towards bryostatin 11. 94

A 5-substituted 2,6-disubstituted -3,6-DHP formed by RCM Scheme 27 Studies towards goniodomin A (94 ). requires alkene substitution on the allylic part of the allylic- homoallylic ether RCM substrate (eg 105 , Scheme 30). 43 In this 2,6-disubstituted -3,6-DHPs bearing further substitution at the 4- synthesis of jerangolid D (107 ), TMSOTf-catalysed three- or 5- positions have been accessed for natural product synthesis component coupling gave an acyclic ether 105 for cis -2,6- using RCM of more substituted alkenes (Schemes 28 −30). In the disubstituted -3,6-DHP 106 formation by RCM. The required synthesis of spliceostatin E (98 ), isopropenylcopper-induced ether 105 was generated by completely diastereoselective regioselective ring-opening of an epoxide 95 , followed by acid- allylation of the oxonium species from the aldehyde 102 and catalysed acetal exchange with acrolein diethyl acetal gave the RCM TMS ether 103 , with the sense of asymmetric induction being substrate 96 (Scheme 28). 41 Cross-metathesis was used to develop rationalised through a Felkin-Anh transition state 104 . the pyranone 97 derived from RCM to the natural product 98 .

TMS H Me TBSO 1. BrMg + HO O TMSO cat. TMSOTf O cat. CuCN OTBDPS OTBDPS OTBS 2. EtO O 102 103 104 95 , PPTS 96 EtO OEt GII (10 mol%) CH 2Cl 2 (0.04 M) GI (2 mol%) reflux, 8 h CH Cl , reflux, 15 h 86% 2 2 TBSO TBSO 1. TBAF O 94% O 2. Swern 106 105 H 3. Ph 3P=CH2 OTBDPS 1. TBAF O O EtO O 4. PCC, AcOH 2. DMP O 97 1 : 1 (α : β) cat. CSA >20 : 1 (α : β) O H O N O MeO O O 107 O O O O O 98 Scheme 30 Synthesis of jerangolid D (107 ).

Scheme 28 Synthesis of spliceostatin E (98 ). The use of RCM to produce 2,3,6-trisubstituted -3,6-DHPs requires assembly of a RCM substrate containing up to 3 In an approach to a bryostatin B-ring building block 101 , RCM stereocentres. In a synthesis of the protein phosphatase 2A involving a MOM enol ether as one of the reacting alkenes was inhibitor phoslactomycin B (111 ) (Scheme 31), 44,45 the required used to form a cis -2,6-disubstituted -3,6-DHP 100 (Scheme 2,3-stereochemistry was set by a [2,3] Wittig rearrangement 42 29). The RCM substrate 99 was prepared by (dr>96:4), where the rearrangement precursor 108 came from Noyori catalytic asymmetric reduction of an ynone (91:9 er).

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Subsequent transacetalisation with acrolein dimethyl acetal not being favoured. However, with a related substrate 115 in a gave the RCM substrate 109 . Relay RCM using GII gave a DHP synthesis of the C13–C34 fragment of ( −) -mucocin (Scheme 110 as an inconsequential 1:1 epimeric mixture. The 33), 46 an allylic silyl ether was also unaffected during RCM, but corresponding acrylate was originally studied in the relay RCM the corresponding allylic alcohol gave 1:1 mixture of step; however, this transformation was found to be difficult. dihydropyran 116 and a cyclooctene 117 . These results show Relay RCM was used in this synthesis to direct initiation, the lower propensity of allylic silyl ethers to engage in potentially avoiding enyne metathesis. metathesis.

O HO O OBn BuLi O OR H TIPS [2,3] Wittig C10 H21 O OH H O O 115 OBn TIPS 108 H H GII (5 mol%) CH 2Cl 2 (5 mM) reflux, 12 h OR OMe HO HO OBn OMe OBn O O O OH + OMe OR C10 H21 O C10 H21 O PPTS H H OBn OBn 109 TIPS TIPS 85% (R = TES) 0% (R = TES) GII (12 mol%) 116 38% (R = H) 117 38% (R = H) CH 2Cl 2 (0.01 M) reflux, 7 h 82% Scheme 33 Synthesis of THP fragment of (−)-mucocin. OMe O HO O P A synthesis of pyranicin (120 ) involved RCM to generate a O O HO O OH 2,3,6-trisubstituted -3,6-DHP 119 (Scheme 34). 47 The RCM substrate 118 was prepared via a double Evans chiral auxiliary TIPS OH approach. The RCM product 119 underwent cross-metathesis 110 111 H2N using HGII to give a triene. While RCM was used to form the DHP ring, the newly formed double bond was not required in Scheme 31 Synthesis of phoslactomycin B (111 ). the product and it, along with the exocyclic alkene from the As mentioned earlier, in a synthesis of ( −) -mucocin (43 ) both cross-metathesis, were hydrogenated using diimide; DHF 42 (Scheme 13) and DHP 114 (Scheme 32) rings were subsequent alcohol deprotections gave pyranicin (120 ). generated using RCM steps.25 Similarly to the DHF RCM O precursor synthesis (Scheme 13), the 2,3,6-trisubstituted -3,6- O BnO Bn BnO DHP precursor 113 was stereoselectively accessed through a N O O N titanium enolate-mediated syn -aldol reaction of a N-glycolyl C12 H25 O oxazolidinone 112 with acrolein. Bn O O

O Bn BnO BnO OTBS

O N C12 H25 O C10 H21 OH C10 H21 O H OTES 118 112 O O GII (10 mol%) benzene (0.1 M) 1. HGII 1. GII (10 mol%) 80 °C, 10 min BnO benzene (10 mM) BnO quant. PMBO 80 °C, 2 h BnO O OTBS C10 H21 O 2. PTSA C10 H21 O O H MeOH H 114 OH 113 OTES C12 H25 O 79% H 2. TsNHNH , NaOAc OTES 119 2 11:1 dr 3. BF 3·OEt 2, Me 2S (−)mucocin HO Scheme 32 Synthesis of a DHP in total synthesis of (−) -mucocin. OH OH O C12 H25 O In the RCM step described above (Scheme 32), non-productive H OH 120 O (reversible) metathesis might be considered to be occurring at the allylic silyl ether site, with 4- or 7-membered ring formation Scheme 34 Synthesis of pyranicin (120 ).

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(–)-Brevisamide (123 ) contains a 2,3,5,6-tetrasubstituted Tf 2NH MeO tetrahydropyran that has been accessed in a stereocontrolled PivO O MeO 48 manner (Scheme 35). A SAE-derived allylic alcohol 121 was OH PivO O O HO H extended with bromoacetic acid to give an N-glycolyl OTBDPS OPMB oxazolidinone 122 that underwent a syn -aldol with acrolein, as 124 OPMB OTBDPS 125 described earlier (Scheme 13). The RCM step involves a 2,2- disubstituted-1-alkene, allowing the final ring stereocentre to be GII (30 mol%) OH installed by stereocontrolled hydrogenation. MeO C B PhMe (0.01 M) HO O O rt, 8 h OH 95% H 1. MsCl, Et N 3 OH O OH O O BnO BnO 2. i. NaI OH ii. Zn dust, I2 121 OH O NaH, Br Cl MeO O O PivO O O Bn O H PivCl, Et 3N MeO O O OPMB BnO N Bn BnO OH OTBDPS O O O 122 N O O Li O HO O 126 O TiCl4, iPr 2NEt HO 2C Bn OH OH 1. LiBH 4 Scheme 36 B and C ring assembly of spirastrellolide A. cat. MeOH O BnO N BnO 2. GII (5 mol%) O O Another example of cyclic ketal-tethered RCM is found in the O CH 2Cl 2 (0.06 M) O o OH 50 40 C, 12 h 1. TBSCl total synthesis of (+)-aigialospirol (130 ) (Scheme 37). (S)- 88% 2. DMP Glycidol (127 ) was converted via a pyrone 128 into the RCM 3. NaBH 4, CeCl 3 4. H2, Pd/C, Et 3N substrate 129 . Although possessing the wrong spirocentre

OH OH stereochemistry at the RCM step, acid-catalysed acetonide H removal at the end of the synthesis resulted in epimerisation O N BnO O O to the natural configuration, stabilised by an intramolecular H- H O TBSO 123 bond between C4-OH and O7.

Scheme 35 Synthesis of (–)-brevisamide (123 ). OH OP OP H H OP O O O H OH O Spiro-, fused- and bridged-3,6-DHP-containing natural products O O have also been approached through RCM-based strategies O 127 128 HO O 129 (Schemes 36 −44). Synthesis of the B ring of the protein O Tf NH O phosphatase 2A inhibitor (+)-spirostrellolide A (126 ) is (P = TBDPS) 2 achieved by cyclic ketal-tethered RCM (Scheme 36). 49 GI (11 mol%) Triflimide-induced ketal formation under stereoelectronic PhMe (7 mM) O rt, 3 h control gives the RCM precursor 125 , where the axially 86% introduced homoallylic alcohol 124 is derived from an HO O OP H O 7 H aldehyde anti -isocrotylation using (−) -(E)- O O crotyldiisopinocampheylborane. O 4 OH O MeO 130 OH O

Scheme 37 Total synthesis of (+)-aigialospirol (130 ).

A fused tetrahydropyran system found in the naturally occurring amino acids dysiherbaine and neodysiherbaine has been made by three RCM-based approaches (Schemes 38−40). In one synthesis of (−) -dysiherbane (133 ) (Scheme 38),51,52 the RCM substrate 132 was constructed by hydroxyl-directed epoxidation of a methyl gylcidate-derived diene 131 , followed by Pd-catalysed epoxide ring-opening with retention, allylation and hydroxymethylation.

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O O furan-derived 8-oxabicyclo[3.2.1]oct-6-ene bearing a 2-exo - VO(acac) 3 allylic ether 136 (Scheme 41). 54 Addition of ethyl vinyl ether at MeO MeO tBuOOH O the end of the RRM poisons the catalyst by formation of a stable OH OH 131 Fisher carbene, preventing undesired post-RRM chemistry. 1. cat. Pd 2(dba)3CHCl 3, PPh 3 2. Ag 2O, allyl bromide

O H H O O H O LDA, H2CO MeO O MeO O H H 132 OH 2:1 dr (major diastereomer shown) GII (4 mol%) CH 2Cl 2 (0.007 M), reflux, 4 h R O H H O O OH HO 2C MeO O O OH H H NH 2 HO C 95% 2 133 R = NHMe dysiherbaine (R = OH neodysiherbaine) Scheme 38 Total synthesis of ( −) -dysiherbaine (133 ). Scheme 41 Synthesis of norhalichondrin B ( 138 ) using RRM. A second route to the 1,5-dioxaoctahydroindene core modifies the Syntheses of 1,3,5-tri-epi-calystegine B 2 (as its 3-O-benzyl RRM chemistry outlined in Scheme 3, by using residual unsaturation derivative 141 ), thromboxane B2 (TXB 2) (146 ) (the stable originating from the dipolarophile component in the [5+2] hydrolysis product of the prostanoid signaling molecule TXA 2), 10 cycloadduct (Scheme 39). and didemniserinolipid B (148 ) all feature RCM steps leading to bridged DHPs (Schemes 42 −44). The strategy to the calystegine GII (10 mol%) H 55 HO H RCM substrate 140 (Scheme 42), involved nitrone formation 1,4benzoquinone (20 mol%) O O ethylene (1 atm) through a sorbose-derived aldehyde condensing with HO CH Cl (0.03 M) O benzylhydroxylamine. The nitrone 139 underwent vinylation and O 2 2 50% H reflux, 3 h chemoselective reduction, leaving the diene functionality intact. Following RCM, hydrogenation with concomitant N-deprotection Scheme 39 Synthesis of the dysiherbaine core using RRM. and then acetonide hydrolysis led to the ring-closed carbinolamine target 141 . A metathesis-induced oxabicyclic rearrangement strategy related to that shown in Scheme 39 allowed a formal synthesis 53 O Bn of dysiherbaine and neodysiherbaine (Scheme 40). The N Cbz metathesis substrate 134 was accessed from Diels-Alder O O N Bn H cycloaddition of a TBS-protected furfuryl alcohol and an Lsorbose O O unsaturated sulfone, followed by resolution. RRM−cross- BnO BnO O O metathesis using HGII in the presence of a large excess of vinyl 139 140 acetate gave a 1,5-dioxaoctahydroindene 135 , with the olefins Bn suitably differentiated to allow progress to dysiherbaine and OH Cbz N GII (9 mol%) OH CH 2Cl 2 (0.2 M) neodysiherbaine. NH BnO OH Microwave irradiation O H HGII (10 mol%) AcO O 100 °C, 1 h O O 141 BnO 79% OAc O O TBSO benzene (0.01 M) O TBSO 60 oC, 4 h H 134 135 Scheme 42 Synthesis of 3-O-benzyl-1,3,5-tri-epi-calystegine B 95% 2 (141 ).

dysiherbaine and neodysiherbaine 56 The route to TXB 2 (146 ) (Scheme 43), used transacetalisation Scheme 40 Domino metathesis step to dysiherbaine and of a unsaturated acetal 142 with a tartaric acid-derived C2- neodysiherbaine. symmetric dienediol 143 to give a pseudo-C2-symmetric RCM substrate 144 , which on RCM with GII led to a bridged In a total synthesis of the marine polyether norhalichondrin B dihydropyran 145 . Subsequent chemoselective cross-metathesis (138 ), a trans -fused pyranopyran 137 was formed by RRM of a involving the terminal olefin allowed homologation for eventual

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conversion to the allylic alcohol side-chain, whereas reagent make to the enol ether RCM substrates from alcohols include: (SAE)-controlled epoxidation of the endocyclic alkene led to alkynylation-carbometallation (Scheme 46), cross-coupling the installation of the unsaturated acid side-chain. enol phosphate of a derived ester (Schemes 47 −48), alkylidenation of a derived ester (Schemes 49 −51), or Hg(II)- OBz OBz catalysed alkoxy exchange with an alkyl vinyl ether (Scheme OH O OEt PPTS 52). benzene O EtO HO 142 143 144 GII (5 mol%) CH 2Cl 2 (2 mM) rt, 19 h CO H 2 73% OH 3 O Scheme 45 RCM approach to 3,4-dihydro-2H-pyrans. 7 O A two-directional approach to the F −J fragment 155 of the HO O OBz 7 4 enantiomer of (+)-gambieric acid A involved RCM chemistry to OH 146 145 form both the G and I rings in one step from the corresponding bis(enol ether) 152 (Scheme 45). 58 The RCM substrate 152 was Scheme 43 Synthesis of thromboxane B (146 ). 2 formed via successive carbocuprations from a bis(alkynyl The strategy to didemniserinolipid B (148 ) (Scheme 44), 57 is ether). Double hydroboration of the RCM product 153 gave a diol for further functionalisation. The F and J rings were also closely related to that for TXB 2, involving ketalisation with the enantiomeric dienediol ent -143 followed by RCM (53%, 81% formed in one step using RCM (154 →155 ). brsm). The use of GI , as opposed to the more active GII , may be to minimize cross-metathesis of the RCM product 147 with the styrene by-product; the presence of the aryl group was necessary to minimise double bond migration in the earlier ketalisation step.

Ph Ph

HO CSA O O benzene HO O

14 14 MsO ent 143 MsO GI (10 mol%) CH 2Cl 2 (3 mM) rt, 40 h OH 53%

H NaO SO O O H O 3 15 O NH 2 O

EtO2C 14 MsO 148 147 Scheme 46 Two-directional approach to gambieric acid A . Scheme 44 Synthesis of didemniserinolipid B (148 ). The strategy of convergent RCM substrate synthesis by Suzuki 3,4-Dihydro-2H-pyrans coupling with an unsaturated ester-derived enol phosphate, seen earlier in a 2,3-DHF approach towards okadaic acid (61 ) Direct formation of 3,4-DHPs 151 by RCM requires an enol (Scheme 16), has also been applied in 3,4-DHP synthesis ether 150 of a bishomoallylic alcohol 149 as the substrate towards the attenol marine toxins (eg, ( −)-attenol A ( 156 ), (Scheme 45). This strategy, followed by elaboration of the enol Scheme 47),59 and the D-ring of (+)-gambieric acid A (157 ) in ether functionality in the RCM product to build fused or spiro the latters first total synthesis (Scheme 48, NAP = 2- ethers, has found significant application in polyether natural napthylmethyl), 60 and (+)-neopeltolide and analogues. 61 product synthesis. Such cases often involve the creation of a 2,3,6-trisubstituted 3,4-DHP 151 by RCM, where the 2,3- substitution is connected as another oxacycle. Methods to

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conditions indicated that with unhindered esters, mainly ester methylenation occurs (giving 150 ) and efficient DHP formation required subsequent addition of a metathesis catalyst such as GII (Schemes 50 −51). More hindered esters predominantly underwent direct DHP formation through alkylidene exchange

(via 159 ) and cyclisation on the ester with loss of “O=TiL n”. Later studies revealed that Ti ethylidene facilitates direct DHP formation also from less-hindered unsaturated esters. While these latter olefinic ester cyclisations (OLECs) are strictly not RCM reactions and theoretically require stoichiometric reagents (in practice large excesses are employed), they are included here for comparison with the two-step procedures and because they offer the advantage of direct access to DHPs from unsaturated esters (Schemes 52 −56).

Scheme 47 RCM −spiroketalisation approach to (−)-attenol A (156 ).

Scheme 49 Possible Ti-alkylidene pathways to 3,4-DHPs 151 .

In a total synthesis of the polycyclic ether marine toxin (−) gamberiol (165 ), both the B and C rings were made using DHPs generated from unsaturated esters (160 and 163 , respectively) by reaction with a Ti methylidene, followed by GII (Scheme 50).63 For the B ring, RCM was carried out on a 1:1 mixture of acyclic and cyclic enol ethers. Subsequent epoxidation with concomitant methanolysis, and then O-allylation followed by Claisen rearrangement (161 →162 ) induced through acid- catalysed elimination of methanol with PPTS on heating, were key steps leading to the unsaturated ester C-ring precursor 163 . For this more hindered ester 163 , the Ti methylidene provided a 8.5:1.5 mixture of acyclic and cyclic enol ethers that was fully converted to the DHP 164 using GII . The Ti methylidene–GII sequence has also been used in the synthesis of A-E fragment of gambieric acid A, forming the D ring as a 2,3,5,6-tetrasubstituted 3,4-DHP.64

Scheme 48 DHP formation by RCM in a total synthesis of (+)- gambieric acid A (157 ).

A popular route to 3,4-DHPs 151 from unsaturated esters 158 uses a reduced titanium alkylidene, derived from TiCl 4 and a 1,1-dibromoalkane (Takai-Utimoto reagent, Scheme 49).62 Initial studies with a Ti methylidene generated under these

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The direct access to DHPs from unsaturated esters by olefinic ester cyclisation (OLEC) using Ti ethylidene has been applied towards several natural products (Schemes 52 −56). The A ring (as well as the 7-membered E ring) of the polycyclic ether marine toxin adriatoxin (174 ) was constructed by esterification, followed by OLEC (Scheme 52);66 70% yield for A ring formation by OLEC (170 →171 ) compares with 50% yield obtained from a more conventional 2-step enol ether−olefin RCM sequence. In contrast, the J ring of adriatoxin was installed, as a C-6 unsubstituted DHP 173 , using GII on a vinyl ether formed from an alcohol 172 using mercuric trifluoroacetate in ethyl vinyl ether.

Scheme 50 Total synthesis of (−)-gambierol (165 ).

In the synthesis of the ABCD trioxadispiroketal subunit 168 of azaspiracid-1 (169 ), a ribose-derived tetrahydrofuran 166 underwent Takai-Utimoto methylenation and the resulting enol ether was purified on neutral alumina (74%) before undergoing RCM with GII to give the C ring 167 (70%, Scheme 51). 65

Scheme 52 OLEC and RCM chemistry towards adriatoxin (174 ).

The R ring of maitotoxin (177 ), a polycyclic ether marine toxin with 32 rings and a molecular weight of 3422 Da, has been made by OLEC (Scheme 53).67 Despite the complexity of the OLEC substrate 175 , assembled from acid chloride and alcohol precursors, formation of the DHP 176 occurred in 93% yield.

Scheme 51 Takai-Utimoto RCM towards ABCD core of azaspiracid-1.

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oxidation to a methoxyketone, and an aldol condensation with methyl glyoxylate.

Scheme 53 OLEC towards maitotoxin (177 ).

Three examples illustrate that a cyclic template is not required for OLECs (Schemes 54 −56). The first example (178 →179 ) forms the central C ring of the marine toxin brevanal (180 ), in 88% yield (Scheme 54); 75% yield was obtained if Takai- Utimoto methylenation was followed by RCM using GII .68 The Scheme 55 Total synthesis of bryostatin 1 (184 ). latter two examples show OLEC applications away from fused polycyclic ether structures containing pyrans (Schemes 55 −56). The spiroacetal core 187 of spirofungin A (188 ) was made by OLEC (185 →186 ) followed, after desilylation by NIS-induced trans-diaxial addition to the DHP and reductive deiodination (Scheme 56).70

Scheme 54 Total synthesis of brevanal (180 ).

The macrolide lactone bryostatin 1 (184 ) is currently in phase

2b clinical trials as a treatment for Alzheimer’s disease. As part of the total synthesis of bryostatin 1 (184 ), a C ring-containing Scheme 56 OLEC towards spirofungin A. enoate fragment 183 was constructed starting from ( R)- isobutyl lactate (Scheme 55). 69 The sequence involved OLEC 3,4-DHPs can also be accessed in a one-flask operation by RCM (181 →182 ), epoxidation (using magnesium of allyl homoallyl ethers to give 3,6-DHPs, followed by catalyst monoperoxyphthalate, MMPP) −methanolytic ring-opening, conversion to a Ru-H to induce alkene isomerisation (cf, Scheme 21) to the enol ether; the natural products centrolobine (90 ) (cf, Scheme 26) and 5,6-dehydro-de-O-

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methyl centrolobine (192 ) (Scheme 57) have been prepared R.J., R.P., N.A.P., C.S. and P.S. are supported by the EPSRC using this strategy. 71 The RCM substrate 190 used in these Centre for Doctoral Training in Synthesis for Biology and syntheses was generated through asymmetric addition of a Medicine (EP/L015838/1), and A.R. by the People Programme chiral allylic silane to an aldehyde 189 (Scheme 57), with the (Marie Curie Actions) of the European Union’s Seventh post-RCM isomerisation being induced by addition of i-PrOH Framework Programme (FP7/2007-2013) under REA grant and NaOH. Completion of the synthesis of 5,6-dehydro-de-O- agreement no 316955. methyl centrolobine (192 ) was achieved from the 3,4-DHP 191 by a regio- and diastereoselective Heck reaction and desilylation. Notes and references 1 G. C. Fu, S. T. Nguyen and R. H. Grubbs, J. Am. Chem. Soc., pBrC 6H4 N 1993, 115 , 9856–9857. Si 2 (a) Olefin Metathesis: Theory and Practice, ed. K. Grela, John N Cl Wiley & Sons, Hoboken, NJ, USA, 2014; (b) Handbook of pBrC 6H4 O HO Metathesis , ed. R. H. Grubbs and D. J O’Leary, Wiley −VCH, 189 Weinheim, Germany, 2015. OTBS er > 98:2 OTBS 3 (a) B. A. Keay, J. M. Hopkins and P. W. Dibble, in NaH Comprehensive Heterocyclic Chemistry III, ed. A. R. Katritzky, Br C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier, GI (5 mol%) Oxford, 2008, vol. 3, pp. 571–623; (b) B. W. Fravel, in PhCH3 (0.1 M) 90 °C, 1 h Comprehensive Heterocyclic Chemistry III, ed. A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier, O then iPrOH, NaOH O Oxford, 2008, vol. 7, pp. 701–726. 191 reflux, 2 h 190 4 M. Bassetti and A. D’Annibale, Curr. Org. Chem ., 2013, 17 , OTBS 93% OTBS 2654–2677. 5 For examples prior to mid-2003, see: A. Deiters and S. F. N BF 1. 2 4 Martin, Chem. Rev. , 2004, 104 , 2199–2238. , cat. Pd(OAc) 2 HO 6 For other recent reviews on RCM, see: (a) Metathesis in 2. TBAF Natural Product Synthesis , ed. J. Cossy, S. Arseniyadis and C. O Meyer, Wiley −VCH, Weinheim, 2010; (b) X. Lei and H Li, Top. 192 Curr. Chem. , 2012, 327 , 163–196; ( c) B. Dassonneville, L. HO OH Delaude, A. Demonceau, I. Dragutan, V. Dragutan, K. S. Etsè and M. Hans, Curr. Org. Chem ., 2013, 17 , 2607–2651; (d) K. Scheme 57 Synthesis of 5,6-dehydro-de-O-methyl centrolobine C. Majumdar, R. K. Nandi and K. Ray, Adv. Org. Syn. , 2013, 6, (192 ) using RCM −isomerisation. 355–435; (e) B. Schmidt, S. Hauke, S. Krehl and O. Kunz, in Comprehensive Organic Synthesis II , ed. P. Knochel and G. A. Molander, Elsevier, Amsterdam, 2014, vol. 5, pp. 1400–1482; Conclusions (f) K. M. Dawood and P. Metz, in Domino Reactions: Concepts for Efficient Organic Synthesis , ed. L. F. Tietze, Wiley −VCH, The structurally constraining demands of natural product Weinheim, Germany, 2014, pp. 31 −66. synthesis provide a challenging environment for synthetic 7 For a recent review on strategies to natural product-related methodology applications. In this review, we have highlighted tetrahydropyrans, see: N. M. Nasir, K. Ermanis and P. A. diverse and inventive applications from the last dozen years of Clarke, Org. Biomol. Chem. , 2014, 12 , 3323 −3335. ring-closing alkene metathesis (RCM) towards the commonest 8 Where published, catalyst loading and substrate concentration for the RCM step are included in the Schemes oxacycles (5 and 6-membered) for use towards such targets. in this review. Despite the many alternative ways available to construct such 9 (a) M. Femenía-Ríos, C. M. García-Pajón, R. Hernández- systems, the fact that RCM has found significant utility in this Galán, A. J. Macías-Sánchez and I. G. Collado, Bioorg. Med. area and in several cases towards highly complex natural Chem. Lett ., 2006, 16 , 5836 −5839; ( b) G. Mancilla, M. products, is a testament to the confidence that the synthetic Femenía-Ríos, M. Grande, R. Hernández-Galán, A. J. Macías- Sánchez and I. G. Collado, Tetrahedron , 2010, 66 , community has in basing a strategy around this methodology. 8068 −8075. The attractiveness of this chemistry stems from a combination 10 P. Escavabaja, J. Viala, Y. Coquerel and J. Rodriguez, Adv. of the flexibility and convergent nature of RCM precursor Synth. Catal., 2012, 354 , 3200 −3204. construction, the range of functional group tolerant catalysts 11 R. Datta, R. J. Dixon and S. Ghosh, Tetrahedron Lett ., 2016, now (commercially) available that react with a variety of 57 , 29 −31. 12 S. Kress and S. Blechert, Chem. Soc. Rev. , 2012, 41 , alkene substitution patterns in a predictable fashion, and the 4389 −4408. scope for post RCM manipulation of the newly formed 13 B. Das, S. M. Mobin and V. Singh, Tetrahedron , 2014, 70 , unsaturation. We hope this review will serve to inspire further 4768 −4777. applications and developments of this chemistry in target- 14 For another spiro-fused example, towards havellockate, see: driven synthesis. R. L. Beingessner, J. A. Farand and L. Barriault, J. Org. Chem. , 2010, 75 , 6337 −6346. 15 A. M. Lone, B. A. Bhat and G. Mehta, Tetrahedron Lett ., 2013, 54 , 5619 −5623. Acknowledgements 16 M. F. Hossain, K. Matcha and S. Ghosh, Tetrahedron Lett ., 2011, 52 , 6473 −6476.

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