Recent Progress in the Synthetic Assembly of 2-Cyclopentenones

Home , Allylic strain, Cyclopentanone, Cyclopentenone

REVIEW ▌1

Recentreview Progress in the Synthetic Assembly of 2-Cyclopentenones David2-Cyclopentenone J. Synthesis Aitken,*a Hendrik Eijsberg,a,b Angelo Frongia,b Jean Ollivier,a Pier Paolo Pirasb a Laboratoire de Synthèse Organique & Méthodologie, ICMMO (CNRS UMR 8182), Université Paris Sud, 15 rue Georges Clemenceau, 91045 Orsay cedex, France Fax +33(1)69156278; E-mail: [email protected] b Dipartimento di Scienze Chimiche e Geologiche, Università degli studi di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, 09042 Monserrato, Cagliari, Italy Received: 09.07.2013; Accepted after revision: 21.08.2013

considerable number of ways in which the target ring sys- Abstract: An overview of the most important synthetic strategies currently available for the preparation of cyclopent-2-enones is pre- tem can be created from acyclic precursors, in either inter- sented and illustrated with recent applications. molecular or intramolecular mode. Most of the possible disconnection strategies have been examined, and it is im- 1 Introduction portant to recognize that for any given target 2-cyclopen- 2 Multicomponent Ring Assembly tenone, there may be several convenient approaches 3 Cyclizations available. The main approaches for ring construction are 4 Transformations of Existing Cyclic Systems summarized graphically in Figure 1. 5 Miscellaneous Methods O (4+1) O O (3+2) (3+2) coupling 6 Conclusions 1 1 1 5 5 2 5 2 2 RCM Key words: cyclopentenones, cyclization, carbocycles, ring clo- (4+1) (3+2) Rautenstrauch 4 3 4 3 4 3 aldol-type annulation sure, rearrangement, annulation (2+2+1) PKR Nazarov (3+2)

Figure 1 The main ring-construction strategies for 2-cyclopentenone synthesis, showing the atom connectivities made during ring as- 1 Introduction sembly (left and center) and cyclization approaches (right). These and other strategies are covered in this review. Scope of this Review 2-Cyclopentenones are a frequently encountered class of Useful procedures based on the transformation of existing cyclic enone. They feature in many areas of organic chem- cyclic structures also exist, as do some miscellaneous istry and serve as benchmark substrates for numerous methods; these will be treated towards the end of this re- chemical transformations, and natural product structures view. containing a 2-cyclopentenone molecular feature are The ‘ideal’ choice of synthetic route depends both on the ubiquitous. specific features in the target skeleton, such as the pres- Some of the synthetic routes to the title compounds have ence of sensitive functional groups or stereogenic centers, been reviewed periodically1 (see also specific sections), and on contextual constraints, such as the employment (or but a global appraisal has not appeared for some time.2 the preclusion) of metals, heat, particular solvents, and so This review covers the literature over the last decade or on. Control of the relative configuration of 4,5-disubsti- so, and it endeavors to provide an overview of the most tuted 2-cyclopentenones can be achieved either by using a commonly used synthetic approaches for assembling the precursor in which those chiral centers are already estab- eponymous core feature from unrelated precursors. It is lished, or by using an approach in which these centers are structured according to the strategy by which the cyclic created in a diastereoselective fashion, such as the enone feature is created, rather than according to any par- Nazarov or related cyclizations. The preparation of nonra- ticular type of derivative or substitution pattern. New ap- cemic 4- and/or 5-substituted 2-cyclopentenones fre- proaches as well as new results using established ones are quently relies on the use of nonracemic chiral substrates. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. considered equally. The use of chiral auxiliaries during the ring-creation process has allowed some asymmetric syntheses to be per- The numerous methods available for the generation of 2- formed, but catalytic enantioselective syntheses are rare at cyclopentenones by α,β-elimination reactions of appropri- present; indeed this might constitute an area of particular ately functionalized cyclopentanone precursors fall out- attention for future developments. side of the scope of this review, as do the vast array of oxidations of cyclopentenes, 2-cyclopentenols and cyclo- Applications of the synthetic approaches reviewed herein pentanones. These limitations notwithstanding, there are a have been selected for illustrative purposes as best as possible, but the quantity of work conducted in the area and SYNTHESIS 2014, 46, 0001–0024 the structural diversity of the molecular targets make it Advanced online publication: 21.11.20130039-78811437-210X unfeasible to present an exhaustive list of synthetic appli- DOI: 10.1055/s-0033-1340414; Art ID: SS-2013-E0467-R cations here. © Georg Thieme Verlag Stuttgart · New York 2 D. J. Aitken et al. REVIEW

Biographical Sketches█

David J. Aitken was born sur-Yvette) he was appoint- ducted in the ICMMO re- in 1963 and studied chemis- ed CNRS researcher at Des- search institute, include the try at the University of cartes University (Paris). In synthesis of functionalized Strathclyde (Glasgow), ob- 1998 he became Professor small-ring compounds, par- taining his PhD in 1986, un- of Organic Chemistry at the ticularly unnatural amino der the supervision of Prof. University of Clermont- acids, as building blocks for H. C. S. Wood and Prof. C. Ferrand, and in 2006 he foldamers and peptidomi- J. Suckling. After a two- transferred to his current po- metics, and synthetic organ- year post-doctoral appoint- sition as Professor at the ic photochemistry. ment with Prof. H.-P. University Paris Sud (Orsay). Husson at the ICSN (Gif- His research interests, con-

Hendrik Eijsberg studied 2008, he joined the group of gliari (Italy) on an organo- at the Ecole Nationale Su- Prof. D. J. Aitken at the Uni- catalysis project. He perieure de Chimie de Paris versity of Paris-Sud (Orsay) finished his PhD in 2012 (France) and carried out un- where he carried out his and joined the group of Pro- dergraduate work on the PhD studies on the photo- fessor I. Marek in the Tech- asymmetric conjugate addi- chemistry of cyclopente- nion Institute (Israel). His tion of organoboron com- nones and alkenes beyond research interests now in- pounds catalyzed by the [2+2] stage. He collabo- clude zirconium-mediated rhodium–diene complexes rated during his PhD with reactions and carbometala- in the group of Prof. J.-P. the group of Prof. P. P. Piras tion of small rings. Genet and Dr. S. Darses. In from the University of Ca-

Angelo Frongia was born tive post-doctoral research Chemistry at the Faculty of in Cagliari (Italy) in 1973. in the group of Prof. D. J. Sciences. His research inter- He graduated and received Aitken in the ICMMO, Uni- ests include asymmetric his PhD degree in Organic versity Paris Sud (Orsay), synthesis and development Chemistry from the Univer- he joined the academic staff of new synthetic methods sity of Cagliari under the su- at the University of Cagliari based on transformation of pervision of Prof. P. P. in 2010. He is currently As- strained organic com- Piras. Following collabora- sistant Professor of Organic pounds.

Jean Ollivier obtained his ences degree in Organic University Paris-Sud. His PhD degree in 1982 at the Chemistry and then spent a research interests include University Paris-Sud (Or- year (1987) as a postdoctor- the chemistry and applica- say) under the direction of al fellow at the Dyson Per- tions of small-ring com- Dr. J. Salaün, then joined rins Laboratory (Oxford) pounds implicating stereo- the Centre National de la with Dr. S. G. Davies. He and enantioselective reac- Recherche Scientifique then returned to Orsay and tions, ring expansions and, (CNRS). In 1986 he ob- is presently Chargé de Re- more recently, organocatal- tained a Doctorat-ès-Sci- cherche in the ICMMO, ysis.

Pier Paolo Piras received 1990–1991 he spent a sab- 2009 he was a Visiting Pro- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. his Laurea in Chemistry at batical year at the Labora- fessor in the University of the University of Cagliari toire des Carbocycles, Paris-Sud (Orsay). His pri- (Italy) in 1971 and began his University of Paris-Sud (Or- mary research interests fo- academic career at the same say) working on cyclopro- cus on the synthesis and university as Assistant Pro- pane derivatives with Dr. J. reactivity of strained carbo- fessor in 1972. He was a Salaün. Returning to Ca- cycles, the synthesis of nat- postdoctoral fellow (1980– gliari, he was appointed As- ural products, and 1981) with Professor C. J. sociate Professor in 1985, asymmetric organocatalytic M. Stirling at the University then full Professor of Or- reactions. of Bangor (North Wales). In ganic Chemistry in 2001. In

Synthesis 2014, 46, 1–24 © Georg Thieme Verlag Stuttgart · New York REVIEW 2-Cyclopentenone Synthesis 3

Overview of 2-Cyclopentenone Reactivity cyclopropanations,24 aziridinations,25 and epoxidations26 While the purpose of this review is to relate the main syn- are also feasible reactions. thetic approaches for the preparation of 2-cyclopentenones, it is useful to present here a brief summary of the chemical reactivity of this molecular core, for two rea- 2 Multicomponent Ring Assembly sons. Firstly, the diversity of chemical transformations that can be carried out thereupon goes some way to ex- 2-Cyclopentenones can be prepared by assembling two or plaining the popularity of the system, and secondly, these more components through the formation of at least two reactivity features should be kept in mind when planning new σ bonds, generally in a sequential fashion. This is a the synthesis of any particular 2-cyclopentenone deriva- versatile and often efficient approach for the construction tive. The core structure is highly reactive, with methods of the target core and it allows for considerable structural available for the modification of every position (Figure 2). diversity. Metal catalysts are often employed. (2+2+1) Ring Assembly reactivity as a carbonyl O The historic example of this type of approach is the nucleophilic reactivity 1 Pauson–Khand reaction, in which a cyclopentenone is 5 reactivity as an enone 2 formed from an alkene and an alkyne in the presence of 3 reactivity at allylic position 4 reactivity as an electron-deficient alkene [Co2(CO)8]. The generally accepted mechanism (Scheme Figure 2 The multiple reactivity profile of the 2-cyclopentenone 1) shows how provision can be made for substituents in all core structure positions. The intermolecular version can be qualified as a (2+2+1) ring assembly. Regioselectivity is an important At the 1-position, the carbonyl group can react in a typical issue, and is dependent on steric factors: usually R1 is larg- manner with nucleophiles that give regioselective 1,2-ad- er than R2. Strained or reactive alkenes are privileged; ditions to conjugated ketones, such as Luche reduction or congested alkenes react less well. The intramolecular ver- addition of organometallic reagents.3 sion – formally a (4+1) assembly, but treated here none- theless – overcomes a good number of the selectivity The 2-position can be functionalized in a number of ways. issues, and provides a versatile entry to polycyclic skele- The conjugate addition of a weak nucleophile to the 3-po- tons. The reaction has been widely studied and consider- sition creates an enolate, which reacts at C2 with carbonyl able synthetic use has been made thereof. Progress has compounds4 or imines5 (in Baylis–Hillman-type reac- been reviewed regularly,27 with particular attention paid tions) or with arylating reagents.6 2-Halocyclopentenones to intramolecular28 and catalytic29 versions, and a compre- can be prepared similarly7 or by other straightforward hensive monograph has appeared very recently.30 means8 and then engaged in carbon–carbon bond-forming Amongst the numerous developments of the Pauson– reactions such as palladium-catalyzed couplings9 or radi- Khand reaction, it is worth noting that complexes of met- cal induced additions.10 2-Cyclopentenone-2-boronic ac- als other than cobalt may serve as catalysts,31 while for- ids can also be prepared for cross-coupling reactions.11 mates or aldehydes can be used as safer CO sources.32 The The 3-position can easily be functionalized via conjugate presence of tertiary amine N-oxides is thought to have an addition of a variety of nucleophiles, both organic12 and accelerating effect, helping in the oxidative removal of heteroatomic,13 and these reactions are often amenable to one CO from the alkyne–cobalt complex. high degrees of enantiomeric control. Heck-type reactions 14 can also be carried out on this position. The tandem se- R1 1 R1 R 4 quence of nucleophilic attack at C3 followed by electro- R Co(CO)3 Co2(CO)8 R2 R3 R2 philic capture of the intermediate enolate at C2 is an Co(CO)3 Co(CO) R3 2 15 – 2 CO elegant route to double functionalization. Co(CO)3 – CO R2 R4 The 4-position can be brominated with N-bromosuccin- R1 R1 Co(CO) imide,16 which opens the way to further functionalization 3 Co2(CO)6 O CO R2 CO R2 17 1 4 Co(CO)3 R R at this position. Vinylogous deprotonation–alkylation O This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. – [Co (CO) ] procedures generally require a heteroatom substituent at R3 R3 2 6 4 4 2 3 the 3-position, as well as conditions which provide the R R R R thermodynamic enolate.18 Scheme 1 The 5-position can react as a typical α carbon to a carbonyl function. The generation of a kinetic enolate allows re- A few recent applications of the Pauson–Khand reaction gioselective electrophilic alkylation at C5.19 Aldolizations are presented here (Scheme 2). Compound 1 was subject- have been described,20 with recent developments allowing ed to a one-pot reduction–lactonization–Pauson–Khand for enantiomeric control.21 reaction to give highly functionalized hydropentalenes 2 with high stereoselectivity.33 Conditions were found for 2-Cyclopentenones are frequent partners in cycloaddition the Pauson–Khand reaction of unactivated alkene 3 with reactions, including photochemical [2+2]-cyclo- additions22 and Diels–Alder reactions.23 Stereoselective alkyne 4 to provide the 2-cyclopentenone 5 on a multigram scale, as the first step in a total synthesis of the ma-

© Georg Thieme Verlag Stuttgart · New York Synthesis 2014, 46, 1–24 4 D. J. Aitken et al. REVIEW rine alkaloids (±)-axinellamines A and B.34 In the Reductive (2+2+1) cyclocarbonylations of internal al- preparation of structural analogues of the anti-cancer ses- kynes require more drastic conditions than those habitual- quiterpene thapsigargin, an intramolecular rhodium- ly employed in the Pauson–Khand reaction, but they have mediated Pauson–Khand reaction was carried out on been achieved using a rhodium catalyst in the presence of allene–alkyne 6 to close a seven-membered ring and give urea under high carbon monoxide pressure (Scheme 4). A product 7 in good yield.35 In a recent evaluation of syn- high diastereomeric excess was observed in the products thetic routes to polycyclic targets, chiral dienediynes 8 11, with cis-isomers arising from dialkylalkynes and were found to undergo highly chemoselective Pauson– trans-isomers from diarylalkynes. In the latter cases, Khand reaction in benzaldehyde, which served as the CO yields were lower due to the formation of a lactone by- 38 source, using [Rh(cod)Cl]2 as the catalyst in the presence product. of racemic BINAP. High cis-diastereoselectivity (up to >20:1) was observed in the products 9, particularly when O O R [RhCl(CO)2]2 bulky substituents were borne adjacent to the chiral cen- (2 mol%) R R R R CO (0.5 MPa) 36 or ter. urea R DMSO, H2O, 130 °C R R R R cis-11 trans-11 H 87–93%, de >93:7 31–55%, de >99:1 a) NaBH3CN R = Et, Bu R = aryl (4 examples) O AcOH O COOEt b) TsOH O Scheme 4 R COOEt R COOEt 1 Co (CO) H (3+2) Ring Assembly 2 8 H (1.2 equiv) O NMO, CH Cl R = various aryl In an effort to overcome some of the limitations of inter- 2 2 9 examples O 54–85% H molecular Pauson–Khand reactions, a number of (3+2) O COOEt dr from 3:1 to 7:1 R ring assemblies have been considered. Construction of the 2 five-membered-ring target has been achieved using most NHBoc Co2(CO)8 of the conceivable disconnections. OTMS (1 equiv) TMSO O NMO, CH2Cl2 Nickel-catalyzed cycloaddition of α,β-unsaturated phenyl 3 5 ethylene glycol esters 12 with internal alkynes provided trisubstituted 2- + NHBoc 4 Å MS 4 up to 58% TMSO OTMS cyclopentenones 13 (Scheme 5). The regioselectivity var- multigram scale ied from poor to excellent, depending on the alkyne used, while terminal alkynes were inefficient substrates. A • 3 [Rh(CO)2Cl]2 mechanism was proposed, implicating a η -oxaallyl (10 mol%) OTr 39 OTr CO (1 atm) phenoxynickel intermediate. O toluene OPMB OPMB 80% OMOM OMOM O 3 O 6 7 R Ni(cod)2 (10 mol%) Cy P (20 mol%) 3 52–91% OPh 3 R R1, R2, R3 = Ph, alkyl H + Zn powder (4 equiv) 1 i 12 examples R 2 PrOH, 130 °C O [Rh(cod)Cl]2 (15 mol%) 12 R R1 R2 rac-BINAP (30 mol%) O O (4 equiv) 13 n PhCHO (20 equiv) OPh 1 1 O R R 80 °C R1 L Ni 8 n n 2 R1 R3 R 9 n = 1 or 2 48–76% R2 R1 = H or Me 9 examples dr from 4:1 2 to >20:1 R = alkyl, aryl, silyl R1 R2

Scheme 2 Scheme 5

A π-allylic precursor can be used instead of the alkyne Nickel-mediated cyclization of alkenyl Fischer carbenes This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. component. For example, reaction of allyl methyl carbon- 14 with internal alkynes40 provided a wide selection of ad- ate with norbornene gave a good yield of the cyclopente- ducts 15 in a highly regioselective manner (Scheme 6). A none adduct 10 with exclusive exo-selectivity (Scheme recent variation employed a chromium alkynylcarbene 16 3).37 and an alkenyl organolithium 17, both of which were prepared from simple precursors. Again, a variety of substi- [RuCl2(CO)3]2 tution patterns were accommodated in the products 18, OCO2Me (2.5 mol%) CO (3 atm) and the method can be adapted for enantioselective cycli- + exo-isomer 41 Et3N, THF, 120 °C zations. Mechanistic models for these transformations O exclusively 80% 10 were proposed by the authors. Scheme 3

Synthesis 2014, 46, 1–24 © Georg Thieme Verlag Stuttgart · New York REVIEW 2-Cyclopentenone Synthesis 5

Cr(CO)5 R3 O ducts which, upon addition of acid, gave transient Ni(cod)2 (1 equiv) R3 protonated vinyl alkenyl ketones that cyclized to chiral 2- OMe + MeCN cyclopentenones 27 in a conrotatory 4π-electron process, R1 2 15 14 R 40–75% R1 R2 44 29 examples in Nazarov fashion (vide infra). It was suggested that this process resulted in axial-to-tetrahedral chirality trans- O 45 Cr(CO) 1) THF fer. In a complementary fashion, reaction of a chiral 5 4 R4 Li R –78 °C to r.t. + 3 lithiated allene 28 with an α-methylcinnamide followed OMe + R 2 3 2) H3O 1 R R by acidic treatment gave the enantiomerically enriched 2- R 1 2 16 50–85% R R 46 18 examples 18 cyclopentenone derivative 29. 17 mostly R3,R4 disubstituted or R2,R3 cyclic examples O OMOM OH Scheme 6 R N Li 2 OMOM • a) THF, –78 °C + TBSO H • Vicinal donor–acceptor disubstituted cyclopropanes are 26 b) aq KH2PO4 H But OTBS t convenient precursors for 1,3-dipoles. The Lewis acid 98% ee OH Bu mediated reaction of cyclopropanes 19 with silyl ynol O ethers gave the [3+2]-cycloaddition adducts which spon- 64% taneously eliminated ethanol to give the cyclopentadienes TBSO But 95% ee 27 20, which required deprotection with hydrofluoric acid to give the corresponding 2-cyclopentenones 21 (Scheme Li OCONR2 OH 42 O 7). OCONR2 • a) toluene, –78 °C NR2 H • + b) 5% HCl–EtOH Ph Ph H t COOEt OSiPr3 COOEt OSiPr3 Bu 28 t Me2AlCl OH Bu + R1 80% ee R2 + R1 O OEt 3 3 R EtO R2 R 74% 19 78% ee Ph But OSiPr3 O 29

EtOOC R3 EtOOC R3 – EtOH HF⋅py Scheme 9 dr >20:1 24–82% R1 R2 R1 2 19 examples R 20 21 An organocatalytic iminium ion/N-heterocyclic carbene Scheme 7 tandem reaction sequence has been used to combine α,β- unsaturated aldehydes and β-keto phenyltetrazolesulfones Zinc chloride promoted a [3+2]-cycloaddition between 30 to give 2,4-disubstituted 2-cyclopentenones 32 in a isoprenyl chloride and methylthio phenylthio ethyne highly enantioselective manner (Scheme 10). Besides the (Scheme 8). The reaction lacked regioselectivity, but the elegance of the sequential organocatalyzed asymmetric two adducts 22 and 23 were separated and transformed Michael addition–benzoin condensation, the judicious in- easily into the corresponding phenylthio 2-cyclopenten- clusion of a phenyltetrazolesulfone (SO2PT) moiety facil- ones 24 and 25 in good yields. The chemistry of the thio- itated a Smiles rearrangement to liberate the target 2- cyclopentenones 32; a rational mechanism for this was ether function was exploited in order to access further 47 derivatives.43 proposed.

O Ar2 O Cl A (5 mol%) B (25 mol%) 2 Ar COOH 2 NaOAc O (10 mol%) Ar a) t-BuOK + (200 mol%) Cl SO PT b) HgCl2 R 2 toluene R O toluene PhS SMe PhS O 30 –30 °C 40 °C 22 24 SO2PT This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ZnCl2 + (1:1) good yields O 75% Cl O Ar PhS SMe a) t-BuOK Smiles Ar 51–69% OH 9 examples b) HgCl2 O SPh R 87–98% ee MeS SPh SO2PT 23 25 31 R 32

Scheme 8 Ar

Ar BF4 N N H N Interesting results have been observed using allenes as ei- A OTMS N Ar = 3,5-(CF ) C H B C6F5 ther the two-carbon or three-carbon component in (3+2) 3 2 6 4 assemblies (Scheme 9). Chiral α-ethers of allenyl carbox- Scheme 10 amides 26 reacted with alkenyllithium reagents to give ad-

Tandem condensation–Wittig cyclization reactions being silyl enol ethers 39 under acidic conditions, revealed tween 2-oxo- or 2,4-dioxo-alkylidinephosphoranes and this to be a convenient and quite general approach for the glyoxals or diacylolefins represent another (3+2) type of preparation of a series of 2-acyl-4-hydroxy-2-cyclopent- assembly leading to cyclopentenones in an efficient man- enones, 40 or 41, respectively (Scheme 12). The base- ner, although cyclohexenone formation may be a compet- mediated reactions required a silica gel treatment to in- ing process. Some aspects of this methodology were duce the cyclization, while the more direct silyl enol ether reviewed recently.48 In the reaction of phosphoranes 33 approach gave slightly lower yields.52 with a series of maleic diesters, the 2-cyclopentenone products 34 were obtained in moderate yields but excel- a) O O 38 49 O O lent diastereoselectivities (Scheme 11). One study was 1 R3 R O 1 = OMe, OEt, OtBu carried out using a chiral sulfoxide derivative of 2-oxo- LDA, THF, –78 °C R1 R R2, R3 = alkyl, aryl 2 O propylidine phosphorane 35, prepared in situ and treated R Δ HO 10 examples b) silica gel, THF, R3 50 R2 with a series of (E)-enediones. In the presence of a key 13–92% 40 copper additive, the Michael addition and subsequent in- TMSO OTMS O O tramolecular Wittig reaction proceeded in a highly regio- 1 3 R1 R = H, Me, Et, OMe O R 2 2 and stereoselective fashion to give the corresponding 3- R R1 R = Me, MOM, OMe, OEt R2 39 R3 = Me or Et methyl-5-sulfoxy-2-cyclopentenones 36. Conditions were 3 O R TiCl , CH Cl HO 10 examples 4 2 2 R3 also established for the facile removal of the sulfoxide ad- 4 Å MS, –78 °C R3 dr from 1:1 to 5:1 juvant, and the resulting 3,4-disubstituted 2-cyclopente- 16–50% 41 nones 37 were obtained with very high enantiomeric Scheme 12 excess (Scheme 11). The reaction of 3-substituted allenoates 42 with symmet- O O O rical diaryl 1,2-diketones in the presence of a phosphine Ph3P OR1 NaH COOR1 R1 = Me, Et gave highly substituted 2-cyclopentenones 43 in excellent 33 R2 = alkyl, allyl + THF, 55 °C 7 examples yields (Scheme 13). The reaction appeared to be highly 2 2 2 R O COOR R OOC COOR2 dr >49:1 diastereoselective although data were not given. The reac- 34 base H2O tion also proceeded with unsymmetrical diones, although O without regioselectivity. A zwitterionic adduct formed O 1 Ph3P COOR from the allene and the phosphine was proposed as the key COOR1 R2O reactive intermediate, which first attacked one carbonyl

2 2 2 with elimination of water then attacked the second car- O COOR R O COOR bonyl with water assistance to induce cyclization.53

O BuLi O COOR2 O O O TDMPP 1 65–96% O R COOR2 THF, –78 °C R Ar (1.5 equiv) 1 Ph3P S R = Me, Ph Ph3P • Ar O Tol + THF, r.t. R2 = Et, tBu O O OH S Li 1 Ar 15 examples *RO Tol 35 ⋅ R 42 Ar CuCN 2LiCl 43 R* = (–)-menthyl TMEDA (1.5 equiv) TDMPP = tris(2,6- –78 °C dimethoxyphenyl)phosphine – H+ O O O – PR3 O O 3 S 3 Ph P PR 3 Zn, AcOH Tol 3 S 3 AcOH 1 2 3 2 PR Tol R COOR R 3P COOR HO 3 MeOH H O 1 2 R COOR2 Me –20 °C Me 46–75% MeOC Ar R1 Ar 37 COR 36 COR COR Ar – H2O O OH Ar 70–88% R = alkyl, allyl Ar O Ar >95% ee 6 examples O

Scheme 11 Scheme 13 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Intermolecular condensations involving classical carban- (4+1) Ring Assembly ion chemistry appear to offer a simple route to the 2-cy- An alternative approach to the 2-cyclopentenone core is a clopentenone core, but side reactions often limit the (4+1) assembly, which has the clear advantage of remov- synthetic utility. Nevertheless, successful applications of ing regioselectivity issues. Carbon monoxide is the obvi- such chemistry do appear. A number of recent papers have ous ‘one-carbon’ component, providing C1 of the target described crossed-aldol condensations between benzil structure, but a few other reagents have been used suc- derivatives and selected ketones to give highly functional- cessfully to provide C3 or C5 when combined with appro- ized 4-hydroxy-2-cyclopentenones, usually as diastereo- priate ‘four-carbon’ partners. isomeric mixtures.51 Carbonylative cyclization of 1,3-butadiene derivatives in A comprehensive study of the cyclization of 1,2-diketones the presence of carbon monoxide has been known for with 1,3-dicarbonyl dianions 38, or with the correspond- some time, and is still considered a pertinent strategy. A

Synthesis 2014, 46, 1–24 © Georg Thieme Verlag Stuttgart · New York REVIEW 2-Cyclopentenone Synthesis 7 series of bicyclic enones 45 was prepared in excellent tained with good trans-stereoselectivity, particularly yields from the appropriate halogeno-dienes 44 using a when the 5-position was monosubstituted.58 palladium catalyst under an atmosphere of carbon monox- 54 O ide (Scheme 14). O X X 55–88% R1 • X R1 R1 = TMS or TIPS (generated in situ) X X, X = (OMe)2, (SPr)2, CO (1 atm) 2 X O R –NPhCH2CH2NPh– Pd(OAc)2 or Pd(dba)2 benzene or Δ R2 R3 (10 mol%) R3 xylene, 8 examples 87–98% 52 53 5 examples BuN4Cl, py, DMF X = Br or I 100 °C Li X 44 45 O 55 O 34–85% TIPS • Bt R X R = H or Me THF, –78 °C TIPS X = heteroatomic function Scheme 14 R Me 9 examples (ZnBr2) Me Me Me dr from 74:26 to >99:1 An interesting recent development is the carbonylation of 54 56 a 1-lithiobutadiene 46 followed by spontaneous cycliza- Scheme 17 tion to give a cyclopentadienyl enolate 47 (Scheme 15). It was shown that this intermediate could be trapped by ac- A selection of stable silyl vinyl ketenes bearing tricarbon- ylation at the γ-position, providing the corresponding 2- ylchromium(0) arene substituents 57 were prepared from cyclopentenone 48 in a one-pot process. However, the Fischer carbene complexes and alkynes, and reacted with system was sensitive to steric factors and α- or O-acyla- diazomethane, or a derivative thereof, to give the (4+1)- tion products were obtained when the 4,5-positions were 55 annulation products 58 in excellent yields and in a com- substituted. pletely stereoselective fashion (Scheme 18).59 Removal of the chromium moiety was subsequently achieved using O O OLi Bu cerium(IV) ammonium nitrate. This process was applied Bu Li Bu Bu CO Li RCOCl in an elegant intramolecular mode, to provide an efficient –78 °C –78 °C Bu Bu Bu Bu synthesis of the rocaglamide skeleton, whereby the Fisch- COR 46 47 48 er carbene alkyne 59 was transformed in a three-step pro- R = Ph, 91% R = tBu, 42% cess into adduct 60 in good yield and complete stereoselectivity (Scheme 18).60 Related studies showed Scheme 15 that the Köbrich reagent (CH2I2 with BuLi) could be used instead of a diazoalkane, while the use of tert-butyl isocy- A titanium-mediated (4+1) assembly of 1,3-butadienes anate provided the 2-cyclopentenone core with an exocy- and nitriles has been described, in which the nitrile acts as clic (Z)-imine moiety at the 5-position.61 the ‘one-carbon’ component.56 Treatment of 2-silyloxy- O butadiene 49 with titanium isopropoxide and a Grignard O • TIPS 2 TIPS R CHN2 reagent gave a titanacyclopentene intermediate which re- 2 1 R acted with a nitrile to give a silyloxycyclopentenylamine R Et2O 1 (CO) Cr (CO)3Cr R 50; spontaneous hydrolysis during work-up led to the cor- 3 OMe MeO 57 62–93% responding 2-cyclopentenone 51 directly (Scheme 16). 58 9 examples single diastereoisomers TIPS i OTMS O a) Ti(O Pr)4 O OTMS iPrMgCl OMe 54–75% TIPS Et2O, –70 °C a) Δ, benzene R = Ph, alkyl, O (ketene formation) b) RCN, –20 °C NH2 chloroalkyl R 4 examples O 49 R Cr(CO)5 b) PhCHN2, Et2O OMe 51 50 59 c) CAN, MeOH 60 Scheme 16 81% (for 3 steps) single diastereoisomer This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Vinyl ketenes are useful intermediates in synthesis and Scheme 18 they can be stabilized to some extent as trialkylsilyl derivatives. A selection of such vinyl ketenes 52 reacted with The reaction of methylenecyclopropanes 61 with Fischer nucleophilic carbenes, generated in situ thermally, to pro- carbene chromium complexes 62 provided 2-cyclopent- vide highly substituted 2-cyclopentenones 53 in good enones 63 in which the ring had been formed from all four yields (Scheme 17).57 In another study, the reaction of vi- of the methylenecyclopropane carbon atoms plus one nyl ketene 54 with selected α-benzotriazolyl (Bt) organo- equivalent of carbon monoxide (Scheme 19). The pro- lithium reagents 55 gave the 2-cyclopentenones 56 in fair posed mechanism involved an initial [2+2]-cycloaddition to good yields, although the addition of a Lewis acid was followed by a rearrangement to give an intermediate al- sometimes necessary to facilitate departure of the Bt kylidinemetallacyclopentane which then underwent CO group (Scheme 17). The products in this case were ob- insertion, chromium elimination, and finally isomerization.62

R3 polarized double bonds) could be harnessed to control the 1 R EtO R3 1 MeOH, H2O R 63 selectivity, and milder reaction conditions were discov- EtO + 70 °C Cr(CO) dr from 1.5:1 ered. Significant recent developments include the use of 2 5 28–58% to 4:1 R R2 O 65 61 62 9 examples organocatalysts and transition-metal-complex cata- [2+2] lysts,66 which open the way to enantioselective reactions isomerization EtO R3 and/or tandem transformation sequences. The Nazarov re- OEt R3 [Cr] 3 R CO 1 action has established itself in the modern synthetic chem- 2 insertion R R EtO R2 – [Cr] ist’s toolbox, and progress has been documented regularly [Cr] R2 O in comprehensive reviews, particularly in the last de- R1 R1 cade,67 and include focuses on catalytic versions,68 asym- Scheme 19 metric versions,69 and alternative routes to the intermediate pentadienyl cation in order to circumvent the highly reactive divinyl ketone substrates.70 Processes in 3 Cyclizations which the cyclopentenyl cation intermediate is intercept- ed by a nucleophile constitute a rich and developing area In this review, ‘cyclization’ implies the formation of a referred to as ‘interrupted Nazarov reactions’, but gener- new ring structure from an acyclic molecule (or from an ally they deviate the reaction course away from 2-cyclo- acyclic fragment of a larger molecule) through the forma- pentenone formation.71 tion of one new σ bond. This definition includes cases where a new π system is generated (or an existing π sys- Only a few of the many recent elegant applications of the tem is shifted) as the σ bond is formed. A comprehensive Nazarov cyclization are presented here (Scheme 21). In a review of ring-closure approaches to cyclopentane deriv- synthesis of (±)-xanthocidin, very fast cyclization of the atives, including some useful precursors of 2-cyclopent- highly substituted divinyl ketone 64 was achieved using enones, appeared recently.63 iron(III) chloride. The sterically challenged oxyallyl cation intermediate underwent exocyclic elimination leading Nazarov Cyclization to the 5-methylene-2-cyclopentenone product 65 in less Arguably one of the most important methods for the prep- than three minutes.72 The preparation of a 2-hydroxycy- aration of 2-cyclopentenones is the acid-promoted cation- clopentenone core can be achieved using a vinyl diketone ic pericyclization of a divinyl ketone, first reported by as the precursor. As part of the total synthesis of (+)-fusi- Nazarov in 1944.64 It is now established that the reaction coauritone, the acidic treatment of the macrobicycle 66 is initiated by acid complexation of the ketone to give a with a Lewis acid gave the requisite tricyclic product 67 pentadienyl cation which undergoes a 4π-electron cycli- with an all-syn stereochemistry.73 The Nazarov cycliza- zation in a conrotatory fashion to provide an oxyallyl cat- tion of the 3-acylated benzofuran 68 was the key step in a ion intermediate. Elimination of a proton followed by short formal synthesis of (±)-methyl rocaglate; while oth- reprotonation of the acid-bound enolate gives the 2-cyclo- er Lewis acids only induced a retro-Friedel–Crafts reac- pentenone product (Scheme 20). tion, acetyl bromide was able to induce cyclization to give 69 in very good yield.74 A chiral Brønsted acid was used A A to catalyze the cyclization of 70 with excellent yield and O O O torquoselectivity, to furnish 71 with 82% ee in a concise conrotatory acid cyclization formal synthesis of (+)-roseophilin. In principle, water is required to trap the oxyallyl intermediate and presumably A O O was furnished by the reagent-grade carbon tetrachloride used as the solvent.75 Copper(II)-complex-mediated cycli- H+

+ – acid zations may be accompanied by skeletal rearrangements, – H again at the oxyallyl cation stage, and such a process was Scheme 20 exploited in a total synthesis of enokipodin B. A bulky bisoxazolidine copper(II) complex induced a sequential cyclization–double-[1,2]-Wagner–Meerwein shift trans- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. The obvious synthetic potential was for some time offset formation of divinyl ketone 72 (as an easily isomerized by selectivity issues, involving the regiochemistry of the mixture, of which only the Z-isomer reacted) to give the proton elimination step and the stereochemistry of the 2-cyclopentenone 73 with impressive regioselectivity, al- enolate protonation step, as well as the harsh acidic condi- though the enantioselectivity was poor.76 tions which were often required. As work progressed, it emerged that steric and/or electronic effects (particularly

Synthesis 2014, 46, 1–24 © Georg Thieme Verlag Stuttgart · New York REVIEW 2-Cyclopentenone Synthesis 9

O O iron-catalyzed formation of the stabilized ylide 78 on the FeCl3 (1 equiv) one hand and base-induced formation of a ketene on the CH Cl , tBuOH TBSO 2 2 other hand. These intermediates reacted together to form i i Pr O Pr r.t., 3 min TBSO iPr 86% 65 a vinyl allenyl ketene 79, which then underwent trifluoro- 64 acetic acid mediated Nazarov cyclization to give the req- i i H Pr H Pr uisite products 80 in good yields and with a high 79 BF3⋅Et2O selectivity for the Z-isomer. O HO

ClCH2CH2Cl, Δ H 77% O O O 66 O 67 Ph3P Fe(TCP)Cl O (0.5 mol%) COCl O • Et3N OMe O N PPh3 OMe 2 2 toluene, r.t. 2 AcBr H R R 1 76 78 Ar R1 Ar R (3 equiv) Ph 77 MeO ClCH2CH2Cl Ph O O 60 °C MeO O O 81% 59–95% 68 OMe 69 1 R = alkyl, Ph TFA 2 OMe R = alkyl, aryl Et2O 2 • 16 examples 1 R R2 R MeO O O OH O O cat* = Ar 1 Z/E from 2.5:1 to 40:1 80 Ar R 79 cat* An (5 mol%) O O CCl4 P Scheme 23 i O NHTf iPr 0 °C Pr 91% An 70 ee 82% 71 An = 9-anthracyl Substrates other than divinyl ketones have been developed for the generation of pentadienyl cations, which fur- O O ther enhances the scope of conrotatory 4π-electron COOMe COOMe (tBox)Cu(SbF6)2 cyclizations. Reactions in this category are commonly re- (1 equiv) ferred to as Nazarov cyclizations, although there is some Δ CH2Cl2, convergence with the Rautenstrauch rearrangement and 72 72% MeO 73 perhaps also with pentadienal cyclizations (vide infra). OMe ee 20% Reduction of vinylalkylidine dioxolanones 81 provided Scheme 21 the corresponding 5-hydroxy-2-cyclopentenones 82 as single diastereoisomers, presumably via conrotatory closure of an intermediate 1,2-oxidopentadienyl cation Treatment of chiral oxazolidinone-derived divinyl ke- 80 tones 74 with methanesulfonic acid gave good yields of (Scheme 24). The strategy was therefore applied in a key transannulation step in a total synthesis of (±)-cephalotax- Nazarov cyclization products 75 as single regioisomers 80 and with excellent diastereoselectivity (Scheme 22).77 A ine. Selective oxidation of alkoxyallenes 83 using di- unique role for the chiral auxiliary was proposed during methyldioxirane provided an entry to oxypentadienyl the cyclization process, whereby two transition-state con- zwitterions, which cyclized in a Nazarov fashion to give formers are involved, each of which progresses with the the bicyclic adducts 84, often as single cis-isomers same torquoselectivity directed by allylic strain.78 (Scheme 24). A mechanism involving diastereoselective epoxidation directed by the difference in the steric bulk of the allene substituents followed by the usual concerted 4π- O O O O O MsOH O electron cyclization was evoked to explain the diastereo- 1 (10 equiv) 81 R N R1 N selectivity. 4 CH2Cl2, 0 °C R 4 2 3 R R 74 R 75–99% 2 3 R R 1 10 examples R 1 1 2 3 75 3 R R , R , R = alkyl, aryl R 3 dr >20:1 R R3 55–95% R4 = Ph or iPr R2 conrotatory R2 O DIBAL-H cyclization R1 R1, R2 = alkyl, aryl H This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O R4 + R3 = H or Me OH toluene R2 O OH hydrolysis 5 examples O O –78 °C during 1 1 O O HO R N R N O work-up O single 82 diastereoisomers R4 O 81 R2 R3 R2 R3 syn anti 40–70% R1, R2 = H or Me OMe OMe Scheme 22 R3 = Ph, alkyl DMDO R1 8 examples R1 • R1 O R2 acetone R3 OMe 0 °C R3 An impressive multi-step one-pot Wittig–Nazarov proto- R2 R3 R2 dr from 3:1 O to single col was conceived for the construction of 4-alkylidene-2- 83 84 diastereoisomers cyclopentenones starting from α-diazoketones 76 and acid chlorides 77 (Scheme 23). The transformation involved Scheme 24

Rautenstrauch Rearrangement OPiv O Ph3PAuOTf OPiv 1 (2–5 mol%) R1 H2O R The palladium(II)-catalyzed isomerization of 1-ethynyl- R3 2-alkenyl acetates to give 2,3-disubstituted 2-cyclopent- MeCN, 25 °C 1 2 82 R 3 2 R3 R 2 R R enones, was first reported in 1984. The proposed mech- R 87 88 anism involves consecutive metal additions to the π- 45–85% systems and migration of acetate, with a hydrolysis step to 7 examples OPiv OPiv O liberate the enone (Scheme 25). Ph3PAuSbF6 R3 (5 mol%) H2O

MeCN, –20 °C AcO AcO 2 2 R 89 R3 R2 R3 R O O 90 ee 79–98% 80–86% [Pd] ee 77–96% [Pd] 5 examples

R OAc OAc AcO [(R,R)-Bnbox O O AcO AuCl2]SbF6 R R H2O (5 mol%) K2CO3 [Pd] • toluene, r.t. MeOH, r.t. 93 91 92 Scheme 25 not isolated 60–69% (unstable) 6 examples

The palladium(II) version of the reaction is still employed Scheme 27 today: in a stereoselective assembly of the ABCE ring system of the natural product azadirachin, the E ring was 3,5-disubstituted or 3,4-fused bicyclic 2-cyclopentenones constructed in this way from the enyne ester 85, giving the 95. It was suggested that tandem gold(I)-catalyzed [3,3]- tetracyclic adduct 86 as a 1:1 mixture of diastereoisomers rearrangement of the substrate and activation of the allen- (Scheme 26).83 ic acetate led to the gold-coordinated allylic cation intermediate, which cyclized as indicated above.86 5-Silyl- O OMe O OCOiPr oxypent-3-en-1-ynes 96 underwent cyclization when PdCl2(MeCN)2 treated with a gold(I) catalyst, to give 2-cyclopentenones AcOH, MeCN 67% 97 in generally good yields. In this case it was proposed

t OMe O that gold complexation of the alkyne induced siloxycycli- COO Bu t OBn COO Bu 85 dr 1:1 OBn 86 dr 1:1 zation followed by carbon–oxygen bond fragmentation to give an allylic carbocation, which subsequently cyclized Scheme 26 at the gold-bound alkenyl site, leading to the substituent topology observed in the final products.87 Most recent developments of this reaction have focused on the use of gold(I) catalysts. A plausible mechanism in- OAc O volves initial formation of an alkyne–gold complex which Ph PAuCl/AgSbF 1 R2 3 6 R R1 (1 mol%) 57–95% undergoes a [1,2]-shift of carboxylate to generate a gold- 8 examples 94 wet CH2Cl2, r.t. R2 coordinated allylic cation, which then evolves by a 95 Nazarov-type cyclization process. The resulting acyloxy cyclopentadiene is hydrolyzed to give the bicyclic prod- R3 OTES O (C6F5)3PAuCl/AgSbF6 2 R1 R (5–10 mol%) uct. The standard process was applied to a series of 1- 44–97% iPrOH (1 equiv) 9 examples ethynyl-2-alkenyl pivaloates 87 to allow access to a wide 3 R 2 1 CH2Cl2, r.t. R range of 3,4- or 3,5-disubstituted 2-cyclopentenones 88 R 96 97 under mild conditions (Scheme 27).84 When a nonracemic Scheme 28

substrate 89 was used, conditions were found in which the This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 3,4-disubstituted products 90 could be obtained with excellent chirality transfer.84 In related work, 1-ethynyl-1- The hydrative rearrangement of 1,1-diethynylcarbinol allenylalkyl acetates 91 underwent cycloisomerization to acetates 98 to 5-acetoxy-2-alkyl-2-cyclopentenones 99 acetoxyfulvenes 92, in the presence of a cationic bisoxa- was achieved using a gold(I) catalyst (Scheme 29). The zolidine–gold(III) complex, that then evolved to provide substrates first underwent a gold-mediated [3,3]-rear- 4-methylene-2-cyclopentenones 93 upon methanolysis.85 rangement to allenyne acetates which then reacted further by gold-induced oxacyclization then nucleophilic attack In further developments of this theme, conjugated enynyl by water. Gold-promoted 5-endo-dig cyclization provided derivatives have been cyclized, again with gold-mediated the cyclic products, accompanied by small amounts of the migration of an oxygen function (Scheme 28). Enynyl allenone by-product 100.88 acetates 94 were treated with a gold(I) complex to give

Synthesis 2014, 46, 1–24 © Georg Thieme Verlag Stuttgart · New York REVIEW 2-Cyclopentenone Synthesis 11

OAc O Ph3PAuCl/AgSbF6 O provide 2-cyclopentenone 104 in 67% yield (Scheme (3 mol%) R 91 R R OAc 31). The use of the Grubbs II catalyst to transform the + H2O/CH2Cl2, r.t. • OAc substrates 105 was more efficient, and provided the series 8 examples 99 98 50–82% 100 of 2- and/or 4-substituted 2-cyclopentenones 106 in excel- 92 Au(I) [3,3]-shift 5-endo-dig Au(I) lent yields. As part of the total synthesis of (–)-heptem- protonation erone B, the ring-closing metathesis reaction of the highly R R Au(I) O H substituted substrate 107 was conducted using Grubbs II • H O OAc oxacyclization, O without incident to give the key intermediate 108, again in attack of water • excellent yield.93 Comparable ring-closing metathesis H O+ 3 processes were used to obtain single enantiomers of Boc- Scheme 29 protected 2- and 5-amino-2-cyclopentenones.94

O OTBS O Hydrative Carbocyclization Grubbs I × In a somewhat different fashion from the reactions de- (2 5 mol%) CH2Cl2, 20 °C scribed above, the hydrative carbocyclization of 1,5-diyn- 67% 104 OTBS 3-ones 101 was achieved using a gold(I) catalyst to fur- 103 O R1 O Grubbs II nish 4-acyl-2-cyclopentenones 102, although other acy- R, R1 = R (1–2.5 mol%) R clic products were obtained as well (Scheme 30). An H, Ph, alkyl Δ CH2Cl2, 5 examples important difference compared to the Rautenstrauch pro- 105 > 95% 106 R1 cess is the absence of oxygen moiety migration, meaning O that the ketone carbon of the substrate was retained as C1 O Grubbs II OBn in the cyclic product. One of the alkyne carbon atoms was (5 mol%) toluene, Δ incorporated as the acyl function in an exocyclic locus in OBn 86% the product structures. It was suggested that the gold- 107 108 mediated hydration of the electron-rich alkyne generated Scheme 31 a gold enolate which then cyclized to a gold cyclopen- tenonyl intermediate.89 Tandem ring-opening and ring-closing procedures have been described within the context of elegant syntheses of R1 Ph PAuCl/AgOTf 3 O 1 complex natural product skeletons (Scheme 32). For the O (3 mol%) R R1, R2 = aryl, alkyl H2O (2 equiv) 3 3 construction of the tricyclic core of tricycloclavulone, 3 R R = Me, -(CH2)5- R 2 dioxane, 25 °C R3 R 7 examples readily available compound 109 was treated with the 3 R 45–73% O 101 R2 102 Grubbs I catalyst to provide the requisite bicyclo[3.3.0] – [Au] 95 [Au] ring system of 110 in good yield. A tandem ring-opening R1 H [Au] and double-ring-closing metathesis protocol was applied R1 H O O O 1 in a total synthesis of (+)-cyanthiwigin U. Starting from H O R 2 3 R3 R [Au] R3 the dialdehyde 111, double vinyl Grignard addition fol- 3 R3 2 R R2 R3 R lowed by oxidation gave the alkene-bis(enone) 112 which R2 [Au] O O was treated immediately with the Grubbs II catalyst to Scheme 30 provide the desired tricyclic product 113 in 43% yield for three steps.96 Ring-Closing Metathesis O H O One of the most important developments in metathesis has Grubbs I (10 mol%) been to provide a tool for the closure of organic ring sys- ethylene, CH2Cl2, r.t. 75% tems. Ring-closing metathesis reactions have been re- H H viewed regularly, notably with regard to their applications 109 110 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. to natural product synthesis.90 Five-membered-ring closure is generally easy, but the reaction is sensitive to elec- OHC a) H2C=CHMgBr, O O H tronic factors, with electron-poor alkenes being less- CeCl3 c) Grubbs II favored substrates. As a result, most ring-closing meta- THF, –78 °C (20 mol%) H b) Dess–Martin ethylene thesis studies have targeted 3-cyclopentenols, although periodinane toluene CHO CH Cl , 0 °C 2 2 O these compounds are often readily oxidized to 2-cyclo- 43% 111 O (for 3 steps) 113 pentenones without difficulty. Here, we report only on 112 ring-closing metathesis reactions that provide 2-cyclopen- Scheme 32 tenones directly. Despite the involvement of a deactivated alkene, the The metathesis reactivity of 2-alkylidene-1,3-dicarbonyls Grubbs I catalyst induced the cyclization of diene 103 to is low; even so, when substrate 114 was subjected to the

2 Grubbs II catalyst, the highly substituted cyclic keto ester R2 Br R Pd(OAc)2 (5 mol%) 65–75% 115 was obtained in an acceptable 65% yield (Scheme Ph P, Et N 3 3 9 examples 1 1 33). With the less bulky substrate 116, the requisite ring- R MeCN, 80 °C R closing metathesis product 117 was obtained in higher 122OH 123 O 97 yield using a lower catalyst loading. Ar Br Pd(OAc) (2 mol%) Ar 2 60–80% Ph3P, Na2CO3 7 examples O O OTBS 124 DMF, 80 °C Grubbs II OH 125 O EtOOC (10 mol%) EtOOC Δ CH2Cl2, Br PdCl (PPh ) (10 mol%) 65% 2 3 2 114 115 OTBS Ph3P, HCOONa 35–48% O 7 examples Grubbs II O DMF, 80 °C EtOOC OH (1 mol%) 126 127 O EtOOC CH2Cl2, Δ 116 82% Scheme 35 117

Scheme 33 the desired 2-cyclopentenone 129 was obtained in high Related to the ring-closing metathesis reaction is the so- yield, opening the way for an expedient total synthesis of called ring-closing enyne metathesis, which can provide a litseaverticillols A and B.102 useful access to vinylcyclopentenes.98 However, the reaction is not efficient with the appropriate precursors for the OTES OTES formation of 2-cyclopentenones (Scheme 34). Cyclization Bu3Sn PdCl2(PPh3)2 (7 mol%) of the alkene-ynone 118 in the presence of Grubbs II cat- EtS (2-furyl)3P O alyst gave the 2-vinyl-2-cyclopentenone 119 in 32% O 91 CuCT (4.5 equiv) yield, while the alternative alkyl-enone mode prevalent THF, MW (80 °C) in 120 (albeit with a deactivated enone) evolved only in 128 90% 129 the presence of titanium(IV) isopropoxide and even then gave a meager 4% yield of the 3-vinyl-2-cyclopentenone Scheme 36 product 121, accompanied by other cross-metathesis products.97 4-Alkynals 130 were converted into 2-cyclopentenones 131 by way of a rhodium(I)-catalyzed intramolecular hy- O OTBS O Grubbs II (15 mol%) droacylation process (Scheme 37). Substituents in any position were compatible with the process, although no 4,5- ethylene, CH2Cl2, 20 °C 32% disubstituted case was examined; acetone was required as 118 119 OTBS the solvent in order to obtain good yields.103 With a coor- O O Grubbs II (5 mol%) dinating methoxy group in the 4-position of the substrates EtOOC i EtOOC Ti(O Pr)4 (0.3 equiv) 132, the employment of a chiral phosphine ligand and a Δ ethylene, ClCH2CH2Cl, noncoordinating solvent, the hydroacylation provided an 120 4% 121 excellent kinetic resolution, giving the enantiomerically Scheme 34 enriched 4-methoxy-2-cyclopentenones 133. The other enantiomers of the substrates 132 were either recovered Other Transition-Metal-Mediated Cyclizations intact, or were converted into the isomeric 2-alkylidene- cyclobutanones 134, depending on the phosphine ligand Intramolecular oxidative Heck coupling has been reported employed.104 using vinyl 2-bromovinyl carbinols 122 as substrates: the 5-endo-trig cyclization gave the 2-cyclopentenones 123 3 O 99 OHC R [Rh(dppe)]2(BF4)2 R1, R2, R3 = directly in decent yields (Scheme 35). With 2-methylal- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (10 mol%) R1 R3 alkyl, alkenyl, alkynyl lyl 2-bromovinyl carbinol substrates 124, the cyclization 2 R acetone 7 examples 100 °C mode switches to 5-exo-trig which furnishes the corre- R1 R2 (no examples with 130 131 2 3 sponding 4,4-dimethyl-2-cyclopentenones 125 in good 67–88% both R and R ) yields.100 Propargyl 2-bromovinyl carbinols 126 have also O O been transformed into 4-methyl-2-cyclopentenones 127, OHC [Rh((R)-Tol-BINAP)]BF4 (5 mol%) R although in this case the yields were modest.101 + CH Cl , r.t. OMe 2 2 OMe The Liebeskind–Srogl coupling reaction was applied in R R = alkyl, aryl OMe 132 133 R 134 6 examples intramolecular mode to a highly functionalized 2-vinyl- 81–88% ee 80–99% ee stannane thioester 128 (Scheme 36). After optimization, Scheme 37

Synthesis 2014, 46, 1–24 © Georg Thieme Verlag Stuttgart · New York REVIEW 2-Cyclopentenone Synthesis 13

Pentadienal Cyclizations CHO R = H, Me, tBu The δ-carbon of a doubly conjugated carbonyl moiety is FeCl (2 equiv) 3 O 3 examples SiMe3 not particularly nucleophilic, and few attempts to effect CH2Cl2 –60 °C to r.t. single cyclization of such compounds had been described until diastereoisomers 139 70–80% recently. A study of the reactivity of simple 2,4-dienals R R 140 135 in the presence of a Lewis acid demonstrated the fea- PtCl2 (5 mol%) sibility of the approach but also revealed some limitations: TsOH (5 mol%) the 2-cyclopentenones 136 were obtained in only modest CHO toluene, 100 °C 105 88% O yields (Scheme 38). The cyclic aliphatic 2,4-dienal 137 141 142 provided the corresponding bicyclic enone 138 in poorer Scheme 39 yield, and the cyclization failed entirely when the γ-methyl group was absent, or when attempted with a triple-conjugated substrate. Several mechanistic possibilities were Intramolecular aldolization of a 1,4-diketone or a 4-keto- suggested, implicating the formation of a cyclopentadiene aldehyde moiety followed by crotonization leads conve- epoxide either by a concerted process or via a Nazarov- like mechanism involving the conrotatory 4π-electron cy- niently to the 2-cyclopentenone core, usually as the clization of an oxypentadienyl cation; isomerization of the thermodynamically preferred structural isomer (Scheme 40). A series of 4,4-spiroannulated 2-cyclopentenones epoxide in the acidic medium would account for the for- 144, inspired in part by the acorone natural product skele- mation of the final products (Scheme 38).105 ton, were prepared from the cyclic keto aldehyde precursors 143 in uniformly good yields regardless of the R existing ring size.108 The final step in the synthesis of a Ar Me2AlCl (0.2 equiv) R = H, Me CH2Cl2, 0 °C Ar R 3 examples model azatriquinane 146 was achieved easily by subject- O 135 25–47% 109 O 136 ing compound 145 to mild basic conditions. Sodium hydride was used to cyclize the diketone 147 to provide Me2AlCl (0.2 equiv) bicyclic derivative 148 in good yield, as part of the first to- O CH2Cl2, 0 °C tal synthesis of (+)-minwanenone.110 The Schöllkopf bis- O 137 22% 138 lactim 149 was used to prepare the unusual α-amino acid 150, featuring the 5,5-disubstituted 2-cyclopentenone concerted O 111 process or moiety, in enantiomerically enriched form. O isomerization cyclization via O pentadienyl R R CHO intermediate R KOH, MeOH n = 1,2,4,8 THF, r.t. 4 examples Scheme 38 n 70–89% n O 143 O 144

O O O An improvement was devised, on the premise that the δ- CHO O NaOMe PhN carbon nucleophilicity would be enhanced by making it a H THF, 0 °C PhN H part of a vinylogous allyl silane system. In the event, when 71% 145 the silylated precursors 139 were treated with a Lewis 146 OTBS acid they provided, after isomerization, the spiro deriva- OTBS tives 140 as single diastereoisomers in good yields NaH, THF (Scheme 39). The excellent diastereoselectivity was ex- r.t. to 65 °C 85% plained by a preferred carbonyl coordination by the Lewis O OMOM OMOM O acid from the less-hindered face of the six-membered 147 O 148 106 iPr ring. In a study of the various cyclization modes possi- iPr MeO ble for the cyclic dienal 141, it was found that platinum(II) MeO N N H2N COOH N chloride in the presence of p-toluenesulfonic acid, the lat- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. N Cs2CO3 OMe OMe ter being used to induce isomerization, drove the reaction MeCN O O O Δ to exclusive formation of the fused 2-cyclopentenone 49% O 150 142.107 149 Base-Induced Annulations Scheme 40 Base-mediated condensations of carbonyl compounds have been a mainstay of organic synthesis for over a cen- A thiol-mediated tandem Michael–aldol reaction of the tury. They are still popular methodologies, notably for the dihydronaphthalene derivatives 151 has been described as construction of cyclic structures, including the title family a route to fused cyclopentenones 152 (Scheme 41). The of compounds. A few recent applications are presented proposed mechanism resembles an intramolecular Baylis– here. Hillman reaction: the thiol adds in a conjugate manner to the α,β-unsaturated ester chain of the bicyclic system,

© Georg Thieme Verlag Stuttgart · New York Synthesis 2014, 46, 1–24 14 D. J. Aitken et al. REVIEW then base-induced condensation of the α-carbanion on the adduct 160 in reasonable yield.116 The oxygen-dependent aldehyde, followed by elimination of the nucleophile and acid-mediated formation of a conjugated iminium ion was prototropy, leads to the 2-cyclopentenone moiety.112 proposed to account for this reaction.

COOR1 O O COOR1 FeSO4 (1 equiv) N N a) HSCH COOMe O (air) 2 O 2 O Et3N, py, 70–80 °C AcOH, 100 °C CHO O 57% b) 20% aq KOH 159 160 0–5 °C 3 O R3 R O 40–60% 2 152 H O R2 151 8 examples R Fe(II) N a) R'SH – H O2 O b) OH COOR1 COOR1 COOR1 R'S R'S – R'SH H H O OH O OH Scheme 43

R3 R3 R3 2 R R2 R2 R1 = Me, Et R'SH = HSCH2COOMe Using the highly functionalized cyclohexanone 161, an R2 = H, Me R3 = H, OMe intramolecular Horner–Wadsworth–Emmons reaction was performed to construct the five-membered ring of 162 Scheme 41 in good yield during a total synthesis of the neurotrophic modulator (±)-jiadifenin (Scheme 44).117 The detailed Other related classical enolate-type condensation proce- study of a range of 2,5-diketophosphonates 163 revealed dures have been used fruitfully in intramolecular mode that the choice of base was critical for the success of the (Scheme 42). With the diketo ester substrate 153, the Horner–Wadsworth–Emmons reaction to provide 164. Knoevenagel reaction was employed to close the five- Furthermore, the by-product 165 resulting from a compet- membered ring in the 5,7,5-tricyclic system of 154 in a to- ing intramolecular aldol reaction was sometimes ob- tal synthesis of (±)-sordaricin.113 A Knoevenagel reaction served, and non-racemic substrates suffered from was also carried out on the polyfunctional hydroxypyra- stereochemical erosion in some cases.118 nones 155, which are masked 4-keto-2-enals. Despite a number of potential condensation paths being available, O O treatment of these compounds with piperidinium acetate O O P(OMe)2 TBSO TBSO gave good yields of the cyclopenta[b]pyran derivatives NaH 156, which were subsequently used to prepare natural O THF, Δ O 114 91% product analogues for cytotoxicity evaluation. The tri- O 161 O 162 ester 157 was converted smoothly into the cyclopent-2- O O enone-5-carboxylic ester derivative 158 by a Dieckmann (MeO)2P O (MeO)2P O cyclization during the initial steps of a short synthesis of O base 115 (–)-kjellmanianone. (different basic R conditions R O R examined) 164 163 165 COOEt COOEt 20–91% H H 6 examples 0–54% O variable ee low ee NaOEt (cat.) O O EtOH, r.t. Scheme 44 H 70% H H 153 OTBS OTBS 154 Other Cyclizations COOtBu R R N HO O HO O H OAc Selected α-(2-chloro-2-propenyl)-α-aryl acetic esters 166 2 O

were cyclized under Friedel–Crafts acylation conditions This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O 4 Å MS, toluene, 50 °C O R = H: 68% 156 COOtBu to give the corresponding 3-chloro-5-aryl-2-cyclopenten- 155 R = Me: 73% ones 167 (Scheme 45). This was the key step in the devel- MeOOC COOMe COOMe opment of a short and general method for obtaining 3,5- NaOMe (2 equiv) 119 COOMe MeOH, 65 °C diaryl-2-cyclopentenones 168. 73% MeO O MeO 157 158 R R R Scheme 42 a) (COCl)2 b) AlCl3 CH Cl , r.t. COOH 2 2 O Suzuki O A novel endocyclic keto-enamine annulation was discov- 8 examples coupling 64–93% Cl ered during a total synthesis of (±)-cephalotaxine Cl Ar (Scheme 43). Treatment of compound 159 with ferrous 166 167 168 sulfate under aerobic conditions provided the pentacyclic Scheme 45

Synthesis 2014, 46, 1–24 © Georg Thieme Verlag Stuttgart · New York REVIEW 2-Cyclopentenone Synthesis 15

The rhodium(II)-mediated decomposition of diazo com- electron ring closure,123 which ensures a trans configura- pounds 169 induced an intramolecular C–H insertion, to tion for the substituent at the 5-position (Scheme 47). In furnish the corresponding cyclopent-2-enone-5-carboxyl- some cases, the acid medium (or more conveniently, basic ic esters 170 as single diastereoisomers in excellent yield, treatment) induces further rearrangement to the more ther- although the reaction failed with an aromatic substituent modynamically stable 2-substituted 4-hydroxy-2-cyclo- in the δ-position (Scheme 46).120 An intramolecular C–H pentenones. Applications of such procedures continue to insertion reaction was applied in the total synthesis of (+)- appear as part of multi-step syntheses.124 przewalskin B, whereby the diazo compound 171 gave the spiro-2-cyclopentenone derivative 172 in good yield OH H O + H2O HO 121 O HO when treated with rhodium(II) acetate. R R (or L.A.) R

O O O R = pentyl, heptyl, OH COOEt Rh2(OAc)4 (1 mol%) CH OTHP HO R COOEt 2 R H R – H CH Cl , 20 °C 3 examples N 2 2 2 single (or base) R 169 82–88% OH R 170 diastereoisomers HO O EtOOC

N2 Scheme 47 O OMOM MOMO Rh2(OAc)4 (2 mol%) O In a large-scale (>0.1 mol) synthesis of 2-normisoprostol, CH2Cl2, 20 °C 89% COOEt a 2-furyl carbinol with an esterified alkyl chain 173 was transformed into the 4,5-disubstituted 2-cyclopentenone 171 172 174 (Scheme 48). Although the ester function was hydro- Scheme 46 lyzed during the reaction and the diastereoselectivity was not established, the yield was essentially quantitative, which was the key feature required of the transforma- 4 Transformations of Existing Cyclic Systems tion.125 The rearrangement of a series of representative fu- ran substrates 175 was examined in water under As stated in the introduction, this review will not cover the microwave conditions (210 °C, 15 bar) without added cat- extensive work done on the transformation of existing cy- alyst: providing the substrate had some miscibility with clopentanoid rings. However, there are some approaches water, reaction times of no more than 15 minutes were to the title compound family that involve the reorganiza- required for good conversions into the corresponding 2- tion of other, non-cyclopentane, ring systems. Two dis- cyclopentenones 176 with excellent anti diastereoselec- tinct categories of reactions can be identified. In one case, tivity.126 some masked chemical reactivity of the cyclic starting material is revealed upon treatment with a specific re- O OH ZnCl2 (5 equiv) agent. Often this implies a 1,4-dicarbonyl intermediate, O COOMe 5 COOH dioxane–H2O, Δ which undergoes aldolization or crotonization, so there is 5 ~100% some overlap with reactions discussed in the section 173 OH 174 above. In the second case, energetic factors are at play in O OH R = H, Ph, Et, H2O the rearrangement of the ring system, either due to inher- O R pentyl, crotyl ent ring strain or photochemical activation. R MW (210 °C, 15 bar) 5 examples 2–15 min dr from 5:1 OH 175 54–96% to 12:1 Rearrangements of Furans and Pyrans 176 Furans are an excellent source of 1,4-dicarbonyl com- Scheme 48 pounds, and the literature on the preparation of these species and their transformations into 2-cyclopentenones up to the mid-1990s were reviewed extensively.122 Furans Furandiols 177 were converted into fused 2-cyclopente- may be conveniently transformed into pyranones via the nones 178 using a catalytic amount of Lewis acid in aque- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 127 Achmatowicz reaction. Alternatively, sugars provide a ous glyme (Scheme 49). The probable mechanism for facile entry to diverse pyran systems. this transformation was an acid-induced spiroketal formation, followed by hydrolysis to a 2-ene-1,4-dione. Intra- 2-Furylcarbinols undergo isomerization to 4-hydroxy-2- molecular aldol condensation of this intermediate cyclopentenones upon treatment with either Brønsted or followed by intramolecular conjugate addition and finally Lewis acids, a process sometimes referred to as the dehydration furnished the bicyclic products. Piancatelli rearrangement. The accepted mechanism involves a series of cationic intermediates, and a final 4π-

OH Ar An unprecedented rearrangement was reported for a poly- Ar ZnCl2 (1 mol%) O functional tetrahydrofuran 185 which was transformed glyme–H2O, Δ OH 70–90% O O into cyclopentenone 186 simply upon standing for five 177 10 examples 178 days (Scheme 52). A mechanism involving an acid- – H O 2 – H2O induced series of intramolecular rearrangements proceeding 132 OH via an acyclic pentadienal intermediate was proposed. OH HO O H O O OH 3 O aldol O OH Br O Ar Ar 5 days Br Ar O HO Ar O O 21 °C 52% Scheme 49 185 186 dr 1:1 Scheme 52 An aza-Piancatelli rearrangement was established, whereby the treatment of 2-furylcarbinols 179 with an aniline in The mild amine-catalyzed rearrangement of pyranones the presence of dysprosium(III) triflate as a catalyst pro- 187 provided trans-4,5-dioxygenated 2-cyclopentenones vided a mild and direct method for the preparation of 4- 188, a reaction which was best explained in terms of an arylamino-2-cyclopentenones 180 (Scheme 50). Only electrocyclic ring opening followed by a conrotatory 4π- trans adducts were obtained and yields were mostly excel- electron cyclization (Scheme 53).133 A similar ring-con- lent, compromised only occasionally by a competing traction process had been observed previously for some 128 Friedel–Crafts alkylation of electron-rich anilines. Re- C2 and C4 ulopyranosides.134 cently, aza-Piancatelli rearrangements were described using as little as 0.03 mol% of phosphomolybdic acid as the O O 129 2 O O catalyst. R 2 R R2 R2 H base H OH O O O O – H conrotatory 1 OH Dy(OTf)3 1 OR OR 1 1 188 O (5 mol%) R R = aryl, alkyl OR OR 187 R + ArNH2 26 examples 1 t 2 MeCN, 80 °C Et3N, MeOH, 60 °C R = Bu; R = Me, Et, Ph 37–56% NHAr DABCO, tBuOH, 60 °C R1 = tBu, iPr, Et, Bn; R2 = H 14–85% 179 33–92% 180

Scheme 50 Scheme 53

In related developments in this area, 2-furaldehyde 181 During the total syntheses of guanacaterenes A and E, a was treated with two equivalents of a secondary amine in cyanohydrin lactone 189, obtained as a mixture of four di- the presence of a lanthanide(III) triflate to provide very astereoisomers in several steps from (+)-carvone, was high yields of the corresponding 4,5-diamino-2-cyclopen- treated with an excess of lithium hexamethyldisilazide to tenones 182, free of the more thermodynamically stable provide a single isomer of a 2-hydroxy-2-cyclopentenone 2,4-isomers (Scheme 51). Here again, a concerted ring- 190 in acceptable yield (Scheme 54). The proposed mech- closure step was invoked to explain the exclusively trans anism involved intramolecular attack of the nitrile-stabi- stereoselectivity.130 Furans bearing donor–acceptor cyclo- lized anion on the lactone to form an epoxyalkoxide, propane substituents 183 have also been used as substrates which then rearranged with expulsion of cyanide to give a for the aza-Piancatelli rearrangement. The reaction pro- 1,2-diketocyclopentane which tautomerized to the most 135 ceeded with either primary or secondary anilines to pro- stable enone structure. vide the functionalized 2-cyclopentenones 184 in good O yields. Excellent diastereoselectivity was also observed, NC O O except when an electron-poor aryl group was present on LiHMDS (3 equiv) OH the cyclopropane substrate.131 THF, r.t. i 55% iPr Pr 189 190 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

O O Ln(OTf) (10 mol%) NC NC O CHO 3 NC O O O O 78–100% Ln = Dy or Sc NR2 + R2NH 8 examples O O O (2 equiv) 4 Å MS 181 MeCN, r.t. single 182 NR2 diastereoisomers iPr i iPr iPr Pr COOMe MeOOC O COOMe Scheme 54 Dy(OTf)3 57–89% O +Ar2NHR (10 mol%) 13 examples 1 COOMe Ar (1 equiv) Ar1 MeCN, r.t. dr from 1:1 (Ar1 e-poor) A simple acid-mediated transformation of 3-methoxycar- NAr2R 1 183 184 to 60:1 (Ar e-rich) bonyl-2-methoxydihydropyrans 191 into the correspond- Scheme 51 ing 3-methoxycarbonyl-2-cyclopentenones 192 was discovered (Scheme 55). The proposed mechanism, sup-

Synthesis 2014, 46, 1–24 © Georg Thieme Verlag Stuttgart · New York REVIEW 2-Cyclopentenone Synthesis 17 ported by an isotopic labelling study, implied the initial with the corresponding compound lacking the hydroxy- elimination of methanol to give a 2H-pyran which under- methyl group at C5.139 An interesting tandem process was went electrocyclic 6π ring-opening to a dienal ester. Prins developed in which allylic substrates 201 were isomerized cyclization followed by elimination of water and isomeri- using photochemically activated iron(0) carbonyl to gen- zation gave the products in moderate yields.136 erate silyl ketal enol ethers 202, which were treated with fluoride to induce ring opening followed by an intramo- O O lecular aldol reaction, to provide the 2-cyclopentenones OMe TsOH (4 equiv) R = alkyl, aryl 140 6 examples 203. MeOH–toluene, 80 °C R COOMe 38–62% R COOMe 191 192 PPh O 3 – H O O – MeOH 2 O O isomerization TBSO TBSO CH2=PPh3 O O H2O HO OO THF TBSO + OH 64% OO O H , H2O –78 °C to r.t. OO Prins R COOMe 195 196 197 R COOMe R COOMe

i O PriO O O Scheme 55 Pr O O Tebbe Me AlCl reagent 2 CH2Cl2 THF, 0 °C –78 °C OOOH OOOH OOOH A novel aza-variant of the pyran-ring-contraction ap- 78% 70% proach has been established for the reaction of 4,6-dial- 198 199 200 kylglycals 193 with aromatic amines in the presence of R R R O Fe(CO) indium bromide, to give trans-2,5-dialkyl-4-arylamino-2- TBSO 5 TBSO O (5 mol%) TBAF O cyclopentenones 194 in fair to good yields (Scheme 56). ν h THF A mechanism was proposed, whereby a Ferrier-type reac- OO THF OO –78°C to r.t. O O tion produced a cyclic aminal intermediate which under- 42–70% 3 examples went indium-mediated ring opening, dehydration, then 201 202 203 137 conrotatory 4π-electron ring closure. Scheme 57

O R2 O 2 Ring Contractions InBr3 (0.3 equiv) R1 R 1 + ArNH2 R = n-alkyl R2 = H, Me HO CH2Cl2, r.t. The photorearrangement of cyclohexa-2,5-dienones to bi- 23 examples 1 33–85% HO R 194 NHAr cyclo[3.1.0]hex-3-en-2-ones is a well-studied transforma- 193 conrotatory tion, and was used to carry out formal syntheses of (±)- [In] [In] cyclization methyleneomycins A and B (Scheme 58). The masked p- 2 2 R2 O NHAr R O NHAr R NHAr benzoquinones 204 were irradiated to furnish 2-cyclopen- H tenones 205 or 206 with a carboxylic ester in either the 4- HO HO O 1 1 R1 R [HO-In] R or 5-position, respectively. After the usual di-π-methane rearrangement from the excited state, the regioselectivity Scheme 56 of the three-membered-ring bond fission of the bicyclic intermediate depends on the presence of a bridgehead sub- Reactions of Sugar Lactones stituent.141 Over the years, ribosides and ribonolactone derivatives have been popular precursors for the preparation of 4,5- O dioxygenated 2-cyclopentenones in single enantiomeric R = CH2OTBS O form. As part of a synthesis of carbon-substituted nucleo- O a cleavage R hν R COOMe sides, a Wittig reagent was added to the silyl enol ether (350 nm) a 42% 205 OMe 195 to generate an intermediate diketophosphorus ylide aq MeOH O

OMe This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. MeO OMe b 60% 196, which cyclized to provide the highly substituted 2- COOMe 138 R = H cyclopentenone 197 in reasonable yield (Scheme 57). 204 b cleavage The enol ether 199 was prepared from a D-ribose deriva- 206 tive 198 by treatment with the Tebbe reagent; its treatment Scheme 58 with dimethylaluminum chloride gave a good yield of the 2-cyclopentenone 200, via a Lewis acid induced isopropyl group cleavage followed by an intramolecular aldol reac- Rearrangements of cyclohexa-2,4-dienones may also lead tion. It had been hoped that the Tebbe reagent might in- to 2-cyclopentenones. When solutions of selected masked duce the rearrangement and thus provide a cascade o-benzoquinones 207 in chloroform were treated with sin- sequence towards some pentenomycin targets; in the glet oxygen followed by thiourea (a reducing agent), the event, dimethylaluminum chloride was the only Lewis anticipated endoperoxides were unexpectedly accompa- acid able to induce the rearrangement, and even this failed nied by 4-hydroxy-2-cyclopentenones 208; these latter products were the only ones obtained when the reactions

OBn were run in methanol (Scheme 59). This ring contraction OBn OBn was proposed to occur via initial formation of the per- O EtO EtO O O a) Me3S(O)I O epoxide intermediate, which underwent an unusual [1,2]- NaH O O 142 Li CO acyl shift in a highly stereoselective manner. N DMF, 0 °C N 2 3 N O O THF, MeOH O Ph b) Sc(OTf)3 50 °C Ph 74% Ph 1 OH Ph 209 Ph 210 Ph R1 OMe R R1 = iPr, R2 = H 211 O , hν OMe 2 COOMe R1 = iPr, R2 = Me Rose Bengal 1 2 t 1 R , R = Bu R + – R1 LiI 1 O O O Me2S CH2 O Δ R MeOH 3 examples 2 THF, 2 R2 O R THF R2 R2 R 70–78% thiourea 208 – HNTsMe 1 R3 –78 °C to r.t. 3 3 207 O2 – MeOH R R – H O 4 NTsMe NTsMe 2 R R4 R4 O O 212 214 O 213 O O R1, R2, R3, R4 = 41–96% 1 1 1 O OMe endo or exo R R 1,2-shift R 10 examples 2 H, alkyl (often cyclic) R R2 OMe OMe OMe 2 O OMe R Scheme 60 O OMe O

Scheme 59

O EtO OH O R1 O HO Ring Expansions Amberlyst 15 Amberlyst 15 R1 Δ 2 Δ TFA, R TFA, 1 Cyclopropanes and cyclobutanes have considerable ring HO 2 R 2 R R2 = Me strain, so rearrangements involving expansion to a five- 216R = H 215 217 49–86% R1 = alkyl 39–54% membered ring are energetically favored. Some reviews 6 examples R2 = H or Me 5 examples on small-ring chemistry have covered formation of 2-cyclopentenones (amongst other compounds) via these Scheme 61 routes.143 2,2-Dichlorocyclobutanes react with diazomethane via a A popular way of conducting a cyclobutanone ring expan- regioselective ring-expansion followed by dehydrochlori- sion is to prepare the corresponding spiroepoxide, then re- nation to give the 2-chloro-2-cyclopentenone framework. arrange it using a Lewis acid. A suitably placed leaving This reactivity was exploited to transform the dichloroke- group is necessary for the extra unsaturation present in 2- tene adduct of 7-methylcycloheptatriene 218 into a single cyclopentenones (Scheme 60). After some optimization hydroazulenone 219 in 76% yield (Scheme 62).147 This studies with a small series of 2-ethoxycyclobutanones, the compound was a key intermediate in the total synthesis of chiral derivative 209 was treated with dimethylsulfoxoni- (±)-6-deoxygeigerin and, later, of (±)-geigerin.148 um methylide to generate a single spiroepoxide which was efficiently ring-expanded in a one-pot procedure using H scandium triflate to give the cyclopentanone 210. Treat- O H a) CH N , Et O ment with base was necessary to eliminate ethanol, and 2 2 2 O the resulting 2-cyclopentenone 211 was then used in the Cl b) DMF, r.t. H 144 Cl 76% Cl syntheses of (+)-carbovir and (+)-aristeromycin. A se- 218 219 lection of protected 2-aminocyclobutanones 212 were Scheme 62 transformed into the corresponding spiroepoxides 213 using dimethylsulfonium methylide. Each of these was smoothly converted into the corresponding 2-cyclopente- The unique chemistry of squaric acid and its derivatives none 214 upon treatment with lithium iodide, via ring ex- has been exploited for selective ring expansions to give 2- pansion and spontaneous β-elimination of the amide cyclopentenones (Scheme 63). Double addition of vinyl fragment. Yields were generally high and the transforma- magnesium bromide to the derivatives 220 proceeded in a tion proceeded with no loss of the stereochemical infor- 1,2-/1,4-fashion to give linear octatetraene species 221, 145 mation derived from the cyclobutanone substrate. which upon selective protonation during work-up under- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. went cyclization to give the polyfunctional derivatives An interesting regioselectivity issue was uncovered dur- 222 in good yield in a one-pot operation.149 ing studies on the ring expansion of 2-hydroxycyclobuta- none aldol adducts 215, using acidic ion-exchange resin BrMgO OMgBr OH RO O (Scheme 61). With no other ring substituents, the skeletal H C CHMgBr 2 RO RO O rearrangement gave the 3-hydroxy-2-cyclopentenone (8 equiv) CF3CH2OH THF, –78 °C RO 216, which is a tautomer of the cyclic 1,3-diketone. On the RO O THF, –78 °C RO H 220 70–84% other hand, with the corresponding 3,3-dimethylated cy- 3 examples 222 i 221 R = Me, Pr, Bu single clobutanones, the acid-mediated rearrangement gave the diastereoisomers 2-hydroxy-2-cyclopentenone regioisomers 217.146 These reaction profiles were interpreted in terms of the relative Scheme 63 migratory aptitudes of the acyl and alkyl groups involved.

A ‘squarate ester cascade’ protocol has been used to congested. With more electron-deficient alkynes, notably struct angular or linear triquinane sequiterpene skeletons acyl derivatives, the reaction evolved differently to give in an elegant fashion (Scheme 64). Sequential addition of 2-vinylcyclobutanones.152 two alkenyllithium species to diisopropyl squarate 223 provided, irrespective of the geometry of the dienolate ad- R O Ru-cat (5 mol%) Ru-cat = In(OTf)3 (5 mol%) duct, an intermediate which evolved first via eight- HO CSA (5 mol%) Ph P membered-ring closure to dienolate 224 then further via Δ 3 Ru THF, Cl Ph3P 68–88% R intramolecular aldol closure to give the linear tricyclic 231 232 R = alkyl structure 225 in 24% yield (after acidic hydrolysis of the 6 examples enol).150 On the other hand, the successive addition of an alkenyllithium then an alkynyllithium to 223 proceeded Scheme 66 via a helical dienolate which ring-closed via a strained intermediate structure 226; the latter then evolved via intra- A ring expansion of highly substituted epoxides bearing molecular enolate attack to close the fused five-membered acetate and propargylic ester functions 233 was achieved ring of 227, in 68% yield. These ring-assembly protocols using a platinum catalyst (Scheme 67). Even though were exploited for the total synthesis of sesquiterpenes. syn/anti mixtures of the substrates were employed, the product 2-cyclopentenones 234 were obtained as single diastereoisomers. The proposed mechanism involved a) O O O i PrO H evolution of a metal–alkyne complex with acetate migra- Li O tion to form a platinum carbene, which reacted with the O iPrO H epoxide to form a pyran 235. An unprecedented tandem O HO b) H2C CHLi 24% O THF, –78 °C O oxa-6π ring opening followed by platinum-mediated con- O (after enol O O O hydrolysis) rotatory 4π-electron ring closure accompanied by acetate 224 iPrO O transposition was proposed to explain the transformation 225 OH 153 223 of the pyran to give the final product 234. This reaction iPrO O is clearly related to the Nazarov and Rautenstrauch cyclization reactions (vide supra). a) iPrO OiPr iPrO OiPr iPrO OiPr Li 3 O O O O OH AcO R3 R O PtCl2(Ph3P)2 (10 mol%) 2 R R2 O b) MeC CLi 68% PhIO (10 mol%) O THF, –78 °C COOR4 toluene, 100 °C OAc 234 R1 233 R1 227 48–73% H COOR4 226 syn/anti mixtures 8 examples single diastereoisomers 4π Scheme 64 R3 cyclization 2 OAc 3 R R [Pt] 2 1-Vinyl-1-silyloxy-2,2-dichlorocyclopropanes 228, easi- O R O O R1 [Pt] COOR4 ly prepared from silyloxydienes, were treated with a sil- 1 R 4 O ver(I) reagent to induce a sequential 2π ring opening and R OOC 3 3 [Pt] 4π-electron ring closure, the latter step being analogous to R R R3 2 R2 OAc R OAc R2 OAc the Nazarov cyclization (Scheme 65). This process pro- oxa-6π O vided chloro-substituted 2-cyclopentenones 229 and 230 1 4 R1 [Pt] COOR4 R O COOR R1 O COOR4 in variable proportions and reasonable yields, albeit with 235 limited control of regio- and diastereoselectivities.151 Scheme 67

Cl O O TIPSO Cl AgBF (1.5 equiv) 4 R2 Cl R2 Cl The treatment of the vicinal diol 236 with strong base pro- R2 CH2Cl2, r.t. +

vided the 2-cyclopentenone 237, reportedly in good yield This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. R1 45–87% 154 R3 R1 R3 R1 (Scheme 68). The transformation is noteworthy as the R3 R1 = H, iPr 228 230 R2, R3 = H, alkyl, Ph 229 first (and so far only) apparent example of an anionic oxy 5 examples retro-ene reaction, giving in this case a diketone enolate Scheme 65 which evolved by intramolecular aldol condensation.

The ring expansion of alkynylcyclopropanols 231 to pro- O HO OK HO OK OH KH vide 3-substituted 2-cyclopentenones 232 was achieved (2 equiv) using a ruthenium catalyst in the presence of indium tri- OH 18-C-6 (2 equiv) H flate and a Brønsted acid (Scheme 66). The reaction was THF, r.t. 'good yield' oxy-retro-ene successful with alkyl-substituted alkynes, for which an in- 236 237 sertion mechanism via a ruthenium metallacycle was sug- Scheme 68

Finally, 1,1-disubstituted spiropentanes 238 were con- O verted into 2-cyclopentenones 239 in the presence of car- iPr FVP (500 °C) bon monoxide and a rhodium catalyst (Scheme 69). The 90% 241 240 O proposed mechanism involved evolution through a series iPr of rhodacycles of increasing size, so that one of the origi- H O MeAlCl (1–1.5 equiv) R2 2 243 nal spiropentane carbons ended up as a methyl substituent maleic anhydride 155 R1 R1 28–92% in an exocyclic locus in the final structure. Two exam- CH Cl , 40 °C 21 examples O 2 2 ples of cyclic-fused 1,2-disubstituted spiropentanes also 242 Z or E R2 predominantly E evolved in a similar fashion with retention of the ring O zeolite junction stereochemistry, albeit in slightly lower yield. R maleic anhydride 86–100% R = alkyl CHCl3, 60 °C 4 examples [RhCl(cod)]2 (5 mol%) R1 244 O O R1 = Me or Ph R 245 DPPP (10 mol%) 2 R R2 = Ph, alkyl R1 2 CO (1 atm) 5 examples R 238 Scheme 70 p-xylene, 130 °C 239 oxidative 76–84% reductive elimination addition isomerization

1 in the final step of a total synthesis of the triquinane natu- R 1 alkyl Rh O CO R 2 migration ral product cucumin E (250) by transformation of the bi- R insertion 2 Rh R R1 160 Rh β -carbon R2 cyclic precursor 249. CO O elimination

O Scheme 69 O 1 COOEt R EtO O R1 THF R1 1 2 + R2 R R Δ –78 °C O O O – CO2 R2 5 Miscellaneous Methods OLi [2+2] O 248 R2 LiO 247 60–89% 246 A few reports of 2-cyclopentenone preparation cannot be 5 examples O conveniently classed in any of the above sections and are H COOEt O therefore collected in this final section. a) OLi H THF, –78 °C The retro-Diels–Alder strategy for the preparation of sub- b) silica gel, H O toluene, Δ stituted 2-cyclopentenones from the tetrahydro-4,7-meth- H O 249 54% 250 ano-1-indanone skeleton was established some time ago, but the cracking conditions required to liberate the target Scheme 71 structures can be somewhat restrictive. Nevertheless, an attractive feature of this approach is the relative ease of In a study of synthetic routes to prostanoids, an unusual access to the starting materials. The approach therefore tandem reaction process was discovered when selected al- continues to enjoy some synthetic applications (Scheme dehydes 251 were transformed into the pyrrolidine en- 70). The preparation of the tri-substituted 2-cyclopenten- amines and heated with 3-iodo-2-methoxymethoxy-1- one 241, a key building block for a proposed total synthe- propene. 4,4-Disubstituted 2-cyclopentenones 252 were sis of the diterpene antibiotic guanacasterpene A, was formed directly, albeit in moderate yields, in what ap- achieved via a flash vacuum pyrolysis (FVP) retro-Diels– peared to be an original domino aza-Claisen–Mannich cy- Alder reaction of 240 in excellent yield.156 In the synthesis clization, terminating in β-elimination of the secondary of selected phytoprostanes for evaluation as PPAR-γ li- amine (Scheme 72). In several cases, the aldehyde sub- gands, a retro-Diels–Alder reaction was performed on tri- strate was a chiral sugar derivative but the spiro adducts cyclic adduct 242 under mild conditions employing a were obtained without significant diastereomeric excess- Lewis acid and an excess of maleic anhydride to trap the es.161 cyclopentadiene by-product. The E-isomer of the 2-cyclopentenone product 243 predominated, regardless of the R2 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 157 configuration (Z or E) of the substrate. Similarly, the OHC OR1 a) R2NH, MeCN, 50 °C OR1 252 36–38% use of zeolites serving as heterogeneous Brønsted acids 2 b) CH =C(OMOM)CH I 251 R 2 2 5 examples facilitated the transformation of a series of tricyclic sub- toluene, 80 °C (R NH = pyrrolidine) O strates 244 into 4-alkyl-2-cyclopentenones 245 under R2NH 2 – R2NH 1 158 1 OR 2 mild conditions. OR R N R N R NR2 2 2 1 R2 2 2 OR The tandem [2+2]-cycloaddition–Dieckmann condensa- N R R 2 1 tion of γ-keto esters 246 with lithium ynolates gave, in the R OR aza- O Mannich MOMO Claisen first instance, bicyclic β-lactones 247, which readily elim- OMe O inated carbon dioxide upon heating to provide 2,3-disub- Scheme 72 stituted 2-cyclopentenones 248 in a one-pot process (Scheme 71).159 An application of this protocol was made

4-Alkylidene-2-cyclopentenones 254 were prepared from enone products 257. On this postulate, mixed condensa- unsaturated 1,4-diketones 253 and selected nitroalkanes tions of aldehydes and enals were carried out using the in a mild tandem ring-closure–Michael addition–elimina- same conditions to give the expected products 258. tion process, with good yields and excellent E-stereoselectivity (Scheme 73).162 This is a surprisingly simple yet O PPh Br attractive route to the target compounds which can other- O 3 2 R R = Me, 68% R R R = Et, 64% wise be difficult to prepare. CH2Cl2, r.t. R 257

2 R 2 O R O O NO 2 DBU (1 equiv) O PPh3Br2 + 1 2 MeCN, r.t. + R R 25–66% 2 CH Cl , r.t. 1 R exclusively 2 2 1 i O R 1 R = Me, Et, Pr Ar 64–93% 1 E isomer R R Ar R2 = H, alkyl 253 16 examples O 254 258 4 examples

– HNO2 Scheme 75 R2 O O O2N R1 Ar R1 Ar 6 Conclusions

Scheme 73 As this review shows, an ever-expanding array of synthetic methodologies is available for the synthesis of 2-cyclo- An intriguing cascade reaction combining benzil (255) pentenones. Established reactions continue to be further and two equivalents of an alkynyllithium has been de- developed while new approaches continue to emerge. scribed, in which it was proposed that the initial 1,5- Some developments emphasize the use of catalytic pro- hexadiyn-3,4-olate adduct evolved via an anionic oxy- cesses or benign reaction conditions, while others priori- Cope rearrangement then an intramolecular aldol conden- tize selectivity issues or other practicalities. A significant sation and a [1,2]-aryl shift, to give 2-phenyl-5-benzoyl- generality to emerge from this overview is that there is no 2-cyclopentenones 256 (Scheme 74). The reaction was one reaction which dominates the scene: the ‘best’ choice substrate-dependent, for competing reaction pathways of synthesis for any given target will depend on a balance were evidenced, but several examples employing an aryl of many factors. Given the enduring importance of the ti- or alkyl acetylide proceeded in high yield. The 5-acyl-2- tle compounds and the efforts currently geared towards cyclopentenone products exhibited the expected keto– their synthesis, it seems likely that methodologies will enol tautomeric equilibria.163 continue to develop at a considerable pace. Finally, an unprecedented cyclotrimerization of α-monosubstituted aldehydes induced by dibromotriphenylphos- Acknowledgment phine has been described (Scheme 75).164 The proposed mechanism consisted of a series of Lewis acid mediated One of us (H.E.) was the beneficiary of a PhD grant (French MESR Allocation) earmarked by Université Paris-Sud for bilateral interna- aldol condensations going via a propenal to give a penta- tional collaboration. The authors are grateful to the Ile-de-France dienal, which isomerized before cyclizing via a Nazarov- region for travel funding (SETCI exchange programme). type process to give the 2,3,5-trisubstituted 2-cyclopent-

Ph Ph Ph Ph Ph R LiO OLi O Ph O LiO OLi O Li anionic Ph + 2 oxy-Cope • • H2O • Ph O 255 Li R R R R R R This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. R R R R R R 75–83% H O R = aryl Ph 2 Ph Ph 3 examples Ph Ph (as keto–enol O O O O tautomeric mixtures) 256 O O Ph

Scheme 74

References (b) Weaving, R.; Roulland, E.; Monneret, C.; Florent, J.-C. Tetrahedron Lett. 2003, 44, 2579. (c) Shi, M.; Zhang, W. (1) (a) Gibson, S. E.; Lewis, S. E.; Mainolfi, N. J. Organomet. Tetrahedron 2005, 61, 11887. Chem. 2004, 689, 3873. (b) Roche, S. P.; Aitken, D. J. Eur. (21) (a) Mizuno, M.; Inoue, H.; Naito, T.; Zhou, L.; Nishiyama, J. Org. Chem. 2010, 5339. (c) Mehta, G.; Srikrishna, A. H. Chem. Eur. J. 2009, 15, 8985. (b) Das, J.; Le Cavelier, F.; Chem. Rev. 1997, 97, 671. (d) Hudlicky, T.; Price, J. D. Rouden, J.; Blanchet, J. Eur. J. Org. Chem. 2011, 6628. Chem. Rev. 1989, 89, 1467. (e) Trost, B. M. Chem. Soc. Rev. (22) (a) Pete, J.-P. In CRC Handbook of Organic Photochemistry 1982, 11, 141. (f) Marsden, S. P. Science of Synthesis; Vol. and Photobiology, 2nd ed.; Horspool, W.; Lenci, F., Eds.; 26; Cossy, J., Ed.; Thieme: Stuttgart, 2004, 1045. CRC Press: Boca Raton, 2003, Chap. 71, 1–14. (b) Le (2) Ellison, R. A. Synthesis 1973, 397. Liepvre, M.; Ollivier, J.; Aitken, D. J. Eur. J. Org. Chem. (3) Coote, S. C.; O'Brien, P.; Whitwood, A. C. Org. Biomol. 2009, 5953. (c) Margaretha, P. In Synthetic Organic Chem. 2008, 6, 4299. Photochemistry; Griesbeck, A. G.; Mattay, J., Eds.; Marcel (4) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. Dekker: New York, 2005, Chap. 8, 211–237. 2010, 110, 5447. (23) (a) Xu, H.; Wolf, C. Angew. Chem. Int. Ed. 2011, 50, 12249. (5) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009, (b) Canales, E.; Corey, E. J. Org. Lett. 2008, 10, 3271. 109, 1. (c) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. (6) Koech, P. K.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 2002, 124, 2458. 5350. (24) (a) Henry, S. S.; Brady, M. D.; Laird, D. L. T.; Ruble, J. C.; (7) Krafft, M. E.; Cran, J. W. Synlett 2005, 1263. Varie, D. L.; Monn, J. A. Org. Lett. 2012, 14, 2662. (8) (a) Smith, A. B. III; Branca, S. J.; Guaciaro, M. A.; (b) Garcia Ruano, J. L.; Alonso, M.; Cruz, D.; Fraile, A.; Wovkulich, P. M.; Korn, A. Org. Synth. 1983, 61, 65. Martin, M. R.; Peromingo, M. T.; Tito, A.; Yuste, F. (b) Kim, K. M.; Chung, K. H.; Kim, J. N.; Ryu, E. K. Tetrahedron 2008, 64, 10546. Synthesis 1993, 283. (c) Adam, W.; Saha-Moeller, C. R.; (25) Menjo, Y.; Hamajima, A.; Sasaki, N.; Hamada, Y. Org. Lett. Zhao, C.-G. Org. React. 2002, 61, 219. 2011, 13, 5744. (9) (a) Negishi, E.-i. Tetrahedron 2000, 56, 10197. (b) Miller, (26) Lee, A.; Reisinger, C. M.; List, B. Adv. Synth. Catal. 2012, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582. 354, 1701. (c) Dyker, G.; Markwitz, H.; Henkel, G. Eur. J. Org. Chem. (27) (a) Schore, N. E. Org. React. 1991, 40, 1. (b) Geis, O.; 2001, 2415. (d) Molander, G. A.; Ham, J.; Seapy, D. G. Schmalz, H.-G. Synthesis 1998, 911. (c) Brummond, K. M.; Tetrahedron 2007, 63, 768. Kent, J. L. Tetrahedron 2000, 56, 3263. (d) Laschat, S.; (10) Liu, K.-M.; Chau, C.-M.; Sha, C.-K. Chem. Commun. 2008, Becheanu, A.; Bell, T.; Baro, A. Synlett 2005, 2547. (e) Lee, 91. H.-W.; Kwong, F.-Y. Eur. J. Org. Chem. 2010, 789. (11) Cho, D. J.; Wu, C. J.; S, S.; Han, W.-S.; Kang, S. O.; Lee, B. (f) Blanco-Urgoiti, J.; Añorbe, L.; Pérez-Serrano, L.; Y. Organometallics 2006, 25, 2133. Domínguez, G.; Pérez-Castells, J. Chem. Soc. Rev. 2004, 33, (12) (a) Morisaki, Y.; Imoto, H.; Hirano, K.; Hayashi, T.; Chujo, 32. Y. J. Org. Chem. 2011, 76, 1795. (b) Thaler, T.; Guo, L.-N.; (28) Gibson, S. E.; Mainolfi, N. Angew. Chem. Int. Ed. 2005, 44, Steib, A. K.; Raducan, M.; Karaghiosoff, K.; Mayer, P.; 3022. Knochel, P. Org. Lett. 2011, 13, 3182. (c) Wei, C.-H.; (29) Shibata, T. Adv. Synth. Catal. 2006, 348, 2328. Mannathan, S.; Cheng, C.-H. J. Am. Chem. Soc. 2011, 133, (30) The Pauson-Khand Reaction: Scope Variations and 6942. (d) Piovesana, S.; Scarpino Schietroma, D. M.; Tulli, Applications; Torres, R. R., Ed.; Wiley: Chichester, 2012. L. G.; Monaco, M. R.; Bella, M. Chem. Commun. 2010, 46, (31) For leading references, see: Wu, N.; Deng, L.; Liu, L.; Liu, 5160. (e) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, Q.; Li, C.; Yang, Z. Chem. Asian J. 2013, 8, 65. 8033. (32) Morimoto, T.; Kakiuchi, K. Angew. Chem. Int. Ed. 2004, 43, (13) (a) Perdicchia, D.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 5580. 3565. (b) Yang, L.; Xu, L.-W.; Zhou, W.; Li, L.; Xia, C.-G. (33) Hong, B. C.; Dange, N. S.; Yen, P.-J.; Lee, G.-H.; Liao, J.- Tetrahedron Lett. 2006, 47, 7723. (c) Rana, N. K.; H. Org. Lett. 2012, 14, 5346. Selvakumar, S.; Singh, V. K. J. Org. Chem. 2010, 75, 2029. (34) Su, S.; Rodriguez, E. A.; Baran, P. S. J. Am. Chem. Soc. (14) (a) Krishna, T. R.; Jayaraman, N. Tetrahedron 2004, 60, 2011, 133, 13922. 10325. (b) Li, J.-H.; Wang, D.-P.; Xie, Y.-X. Tetrahedron (35) Tap, A.; Jouanneau, M.; Galvani, G.; Sorin, G.; Lannou, M.- Lett. 2005, 46, 4941. I.; Ferezou, J.-P.; Ardisson, J. Org. Biomol. Chem. 2012, 10, (15) Guo, H.-C.; Ma, J.-A. Angew. Chem. Int. Ed. 2006, 45, 354. 8140. (16) Gerdil, R.; Liu, H.; Bernardinelli, G. Helv. Chim. Acta 1999, (36) Turlington, M.; Du, Y.; Oqtrum, S. G.; Santosh, V.; Wren, 82, 418. K.; Lin, T.; Sabat, M.; Pu, L. J. Am. Chem. Soc. 2011, 133, (17) (a) Kelly, J. M.; Leeper, F. J. Tetrahedron Lett. 2012, 53, 11780.

819. (b) Tolstikov, G. A.; Miftakhov, M. S.; Danilova, N. (37) Morisaki, Y.; Kondo, T.; Mitsudo, T.-A. Org. Lett. 2000, 2, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. A.; Vel’der, Ya. L.; Spirikhin, L. V. Synthesis 1989, 625. 949. (18) (a) Demir, A. S.; Enders, D. Tetrahedron Lett. 1989, 30, (38) Huang, Q.; Hua, R. Chem. Eur. J. 2009, 13, 3817. 1705. (b) Mukaiyama, T.; Ohsumi, T. Chem. Lett. 1983, (39) Ohashi, M.; Taniguchi, T.; Ogoshi, S. J. Am. Chem. Soc. 875. (c) Lakhvich, F. A.; Lis, L. G.; Pap, A. A.; Rubinov, D. 2011, 133, 14900. B.; Zheldakova, T. A.; Akhrem, A. A. Zh. Org. Khim. 1988, (40) Barluenga, J.; Barrio, P.; Riesgo, L.; López, L. A.; Tomás, 24, 518. M. J. Am. Chem. Soc. 2007, 129, 14422. (19) (a) Schulé, A.; Liang, H.; Vors, J.-P.; Ciufolini, M. A. J. (41) Barluenga, J.; Álvarez-Fernández, A.; Suárez-Sobrino, Á. Org. Chem. 2009, 74, 1588. (b) Altenbach, R. J.; Brune, M. L.; Tomás, M. Angew. Chem. Int. Ed. 2012, 51, 183. E.; Buckner, S. A.; Coghlan, M. J.; Daza, A. V.; Fabiyi, A.; (42) Qi, X.; Ready, J. M. Angew. Chem. Int. Ed. 2008, 47, 7068. Gopalakrishnan, M.; Henry, R. F.; Khilevich, A.; Kort, M. (43) Miller, J. A.; Pugh, A. W.; Ullah, G. M.; Welsh, G. M. E.; Milicic, I.; Scott, V. E.; Smith, J. C.; Whiteaker, K. L.; Tetrahedron Lett. 2001, 42, 955. Carroll, W. A. J. Med. Chem. 2006, 49, 6869. (44) Tius, M. A. Acc. Chem. Res. 2003, 36, 284. (20) (a) Kobayashi, Y.; Murugesh, M. G.; Nakano, M.; Takahisa, E.; Usmani, S. B.; Ainai, T. J. Org. Chem. 2002, 67, 7110.

(45) Hu, H.; Smith, D.; Cramer, R. E.; Tius, M. A. J. Am. Chem. (69) Shimada, N.; Stewart, C.; Tius, M. A. Tetrahedron 2011, 67, Soc. 1999, 121, 9895. 5851. (46) Schultz-Fademrecht, C.; Tius, M. A.; Grimme, S.; (70) Spencer, W. T. III; Vaidya, T.; Frontier, A. J. Eur. J. Org. Wibbeling, B.; Hoppe, D. Angew. Chem. Int. Ed. 2002, 41, Chem. 2013, 3621. 1532. (71) Grant, T. N.; Rieder, C. J.; West, F. G. Chem. Commun. (47) Jacobsen, C. B.; Jensen, K. L.; Udmark, J.; Jørgensen, K. A. 2009, 5676. Org. Lett. 2011, 13, 4790. (72) Yaji, K.; Shindo, M. Tetrahedron 2010, 66, 9808. (48) Feist, H.; Langer, P. Synthesis 2008, 3877. (73) Williams, D. R.; Robinson, L. A.; Nevill, C. R.; Reddy, J. P. (49) Langer, P.; Kracke, B. Synlett 2001, 1790. Angew. Chem. Int. Ed. 2007, 46, 915. (50) Shinohara, Y.; Kurata, T.; Kitano, H.; Matsumoto, K.; (74) Magnus, P.; Freund, W. A.; Moorhead, E. J.; Rainey, T. Takahashi, I.; Hosoi, S.; Ota, T.; Hatanaka, M. Synlett 2002, J. Am. Chem. Soc. 2012, 134, 6140. 1245. (75) Kerr, D. J.; Flynn, B. L. Org. Lett. 2012, 14, 1740. (51) (a) Cai, X.-h.; Xie, B. Res. J. Chem. Sci. 2011, 1, 120. (76) Lebœuf, D.; Wright, C. M.; Frontier, A. J. Chem. Eur. J. (b) Marjani, K.; Mohsen, M.; Arazi, A.; Ashouri, A.; 2013, 19, 4835. Bourghani, S.; Rajabi, M. Monatsh. Chem. 2009, 140, 1331. (77) Kerr, D. J.; Miletic, M.; Chaplin, J. H.; White, J. M.; Flynn, (c) Marjani, K.; Mousavi, M.; Ashouri, A.; Arazi, O.; B. L. Org. Lett. 2012, 14, 1732. Bourghani, S.; Asgari, M. J. Chem. Res. 2008, 398. (78) Flynn, B. L.; Manchala, N.; Krenske, E. H. J. Am. Chem. (d) Majani, K.; Asgari, M.; Ashouri, A.; Mahdavinia, G. H.; Soc. 2013, 135, 9156. Ahangar, H. A. Chin. Chem. Lett. 2009, 20, 401. (79) Cao, P.; Sun, X.-L.; Zhu, B.-H.; Shen, Q.; Xie, Z.; Tang, Y. (52) Holtz, E.; Köhler, V.; Appel, B.; Langer, P. Eur. J. Org. Org. Lett. 2009, 11, 3048. Chem. 2005, 532. (80) Li, W.-D. Z.; Duo, W.-G.; Zhuang, C.-H. Org. Lett. 2011, (53) Jose, A.; Lakshmi, K. C. S.; Suresh, E.; Nair, V. Org. Lett. 13, 3538. 2013, 15, 1858. (81) Spencer, W. T. III; Levin, M. D.; Frontier, A. J. Org. Lett. (54) Gagnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 2011, 13, 414. 4804. (82) Rautenstrauch, V. J. Org. Chem. 1984, 49, 950. (55) Li, H.; Liu, L.; Zhao, F.; Wang, C.; Wang, C.; Song, Q.; (83) Nakagawa, D.; Miyashita, M.; Tanino, K. Tetrahedron Lett. Zhang, W.-X.; Xi, Z. J. Org. Chem. 2012, 77, 4793. 2010, 51, 2771. (56) Laroche, C.; Bertus, P.; Szymoniak, J. Chem. Commun. (84) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 2005, 3030. 127, 5802. (57) Rigby, J. H.; Wang, Z. Org. Lett. 2003, 5, 263. (85) Kato, K.; Kobayashi, T.; Fujimami, T.; Motodate, S.; (58) Davie, C. P.; Danheiser, R. L. Angew. Chem. Int. Ed. 2005, Kusakabe, T.; Mochida, T.; Akita, H. Synlett 2008, 1081. 44, 5867. (86) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442. (59) Moser, W. H.; Feltes, L. A.; Sun, L.; Giese, M.; Farrell, R. (87) An, S. E.; Jeong, J.; Baskar, B.; Lee, J.; Seo, J.; Rhee, Y. H. W. J. Org. Chem. 2006, 71, 6542. Chem. Eur. J. 2009, 15, 11837. (60) Giese, M.; Moser, W. H. Org. Lett. 2008, 10, 4215. (88) Oh, C. H.; Karmakar, S. J. Org. Chem. 2009, 74, 370. (61) Li, Z.; Moser, W. H.; Deng, R.; Sun, L. J. Org. Chem. 2007, (89) Tang, J.-M.; Liu, T.-A.; Liu, R.-S. J. Org. Chem. 2008, 73, 72, 10254. 8479. (62) Kurahashi, T.; Wu, Y.-T.; Meindl, K.; Rühl, S.; de Meijere, (90) (a) Prunet, J. Eur. J. Org. Chem. 2011, 3634. (b) Metathesis A. Synlett 2005, 805. in Natural Product Synthesis; Cossy, J.; Arseniyadis, S.; (63) Kurteva, V. B.; Afonso, C. A. M. Chem. Rev. 2009, 109, Meyer, C., Eds.; Wiley-VCH: Weinheim, 2010. 6809. (c) Monfette, S.; Fogg, D. E. Chem. Rev. 2009, 109, 3783. (64) Nazarov, I. N.; Zaretskaya, I. I. Izv. Akad. Nauk. SSSR, Ser. (d) Majumdar, K. C.; Muhuri, S.; Islam, R.; Chattopadhyay, Khim. 1944, 65. B. Heterocycles 2009, 78, 1109. (e) Chattopadhyay, S. K.; (65) (a) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Nachtsheim, B. J. Angew. Chem. Int. Ed. 2007, 46, 2097. Roy, B. Tetrahedron 2007, 63, 3919. (f) Villar, H.; Frings, (b) Basak, A. K.; Shimada, N.; Bow, W. F.; Vicic, D. A.; M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55. (g) Brown, R. Tius, M. A. J. Am. Chem. Soc. 2010, 132, 8266. (c) Bow, W. C. D.; Satcharoen, V. Heterocycles 2006, 70, 705. E.; Basak, A. K.; Jolit, A.; Vicic, D. A.; Tius, M. A. Org. (h) Schmidt, B.; Hermanns, J. Curr. Org. Chem. 2006, 10, Lett. 2010, 12, 440. (d) Rueping, M.; Ieawsuwan, W. Chem. 1363. (i) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, Commun. 2010, 11450. 2199. (j) Han, S. Y.; Chang, S. In Handbook of Metathesis; (66) (a) Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927. Vol. 2; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2010, (b) Aggarwal, V. K.; Belfield, A. J. Org. Lett. 2003, 5, 5075. Chap. 2, 5–127. (c) Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, (91) Funel, J.-A.; Prunet, J. J. Org. Chem. 2004, 69, 4555.

9544. (d) Janka, M.; He, W.; Haedicke, I. E.; Fronczek, F. (92) Dübon, P.; Schelwies, M.; Helmchen, G. Chem. Eur. J. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. R.; Frontier, A. J.; Eisenberg, R. J. Am. Chem. Soc. 2006, 2008, 14, 6722. 128, 5312. (e) Cao, P.; Deng, C.; Zhou, Y.-Y.; Sun, X.-L.; (93) Miller, A. K.; Hughes, C. C.; Kennedy-Smith, J. J.; Gradl, S. Zheng, J.-C.; Xie, Z.; Tang, Y. Angew. Chem. Int. Ed. 2010, N.; Trauner, D. J. Am. Chem. Soc. 2006, 128, 17057. 49, 4463. (94) (a) Davis, F. A.; Wu, Y. Org. Lett. 2004, 6, 1269. (67) (a) Pellissier, H. Tetrahedron 2005, 61, 6479. (b) Frontier, (b) Bullock, K.; Chong, P.; Davies, R.; Elitzin, V.; Hatcher, A. J.; Collinson, C. Tetrahedron 2005, 61, 7577. (c) Tius, M. M.; Jackson, M.; Liu, B.; Patterson, D.; Powers, J.; Salmons, A. Eur. J. Org. Chem. 2005, 2193. (d) Habermas, K. L.; M.; Tabet, E.; Toczko, M. Top. Catal. 2012, 55, 446. Denmark, S. E. Org. React. 1994, 45, 1. (e) Denmark, S. E. (95) Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563. In Comprehensive Organic Synthesis; Vol. 5; Paquette, L. (96) Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, A., Ed.; Pergamon: Oxford, 1991, 751–784. (f) Santelli- 127, 5334. Rouvier, C.; Santelli, M. Synthesis 1983, 429. (97) Toueg, J.; Prunet, J. Synlett 2006, 2807. (68) Vaida, T.; Eisenberg, R.; Frontier, A. J. ChemCatChem (98) Diver, S. T.; Guissert, A. J. Chem. Rev. 2004, 104, 1317. 2011, 3, 1531.

(99) Ray, D.; Paul, S.; Brahma, S.; Ray, J. K. Tetrahedron Lett. (134) (a) Zou, W.; Shao, H.; Wu, S.-H. Carbohydr. Res. 2004, 2007, 48, 8005. 339, 2475. (b) Zou, W.; Wang, Z.; Lacroix, E.; Wu, S.-H.; (100) Ray, D.; Ray, J. K. Org. Lett. 2007, 9, 191. Jennings, H. J. Carbohydr. Res. 2001, 334, 223. (101) Ray, D.; Mal, S. K.; Ray, J. K. Synlett 2005, 2135. (135) Shipe, W.; Sorensen, E. J. J. Am. Chem. Soc. 2006, 128, (102) Morita, A.; Kuwahara, S. Org. Lett. 2006, 8, 1613. 7025. (103) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 11492. (136) Matoušová, E.; Růžička, A.; Kuneš, J.; Králová, J.; Pour, M. (104) (a) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 124, Chem. Commun. 2011, 47, 9390. 10296. (b) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2003, (137) Li, F.; Ding, C.; Wang, M.; Yao, Q.; Zhang, A. J. Org. 125, 9078. Chem. 2011, 76, 2820. (105) Miller, A. K.; Banghart, M. R.; Beaudry, C. M.; Suh, J. M.; (138) Pryde, D. C.; Middleton, D. S.; Stephenson, P. T.; Trauner, D. Tetrahedron 2003, 59, 8919. Wainwright, P.; Maddaford, A.; Zhang, X.; Leese, D.; Glen, (106) Kuroda, C.; Honda, S.; Nagura, Y.; Koshio, H.; Shibue, T.; R.; Hart, J.; Forrest, N.; Guyot, T. Tetrahedron Lett. 2011, Takeshita, T. Tetrahedron 2004, 60, 319. 52, 6415. (107) Lo, C.-Y.; Lin, C.-C.; Cheng, H.-M.; Liu, R.-S. Org. Lett. (139) Kumar, B. S.; Mishra, G. P.; Rao, B. V. Tetrahedron Lett. 2006, 8, 3135. 2013, 54, 2845. (108) Srikrishna, A.; Kumar, P. P. Tetrahedron 2000, 56, 8189. (140) Petrignet, J.; Prathap, I.; Chandrasekhar, S.; Yadav, J. S.; (109) Pearson, A. J.; Kim, E. H.; Sun, H. Tetrahedron 2010, 66, Grée, R. Angew. Chem. Int. Ed. 2007, 46, 6297. 4943. (141) Hong, F.-T.; Lee, K.-S.; Liao, C.-C. J. Chin. Chem. Soc. (110) Mehta, G.; Shinde, H. M. Tetrahedron Lett. 2007, 48, 8297. 2000, 47, 77. (111) Andrei, M.; Undheim, K. Tetrahedron: Asymmetry 2004, (142) Kao, T.-C.; Chuang, G. J.; Liao, C.-C. Angew. Chem. Int. Ed. 15, 53. 2008, 47, 7325. (112) Samanta, S.; Yasmin, N.; Kundu, D.; Ray, J. K. Tetrahedron (143) (a) Leemans, E.; D’hooghe, M.; De Kimpe, N. Chem. Rev. Lett. 2010, 51, 4132. 2011, 111, 3268. (b) Mack, D. J.; Njardarson, J. T. ACS (113) Kitamura, M.; Chiba, S.; Narasaka, K. Chem. Lett. 2004, 33, Catal. 2013, 3, 272. 942. (144) Brown, B.; Hegedus, L. S. J. Org. Chem. 2000, 65, 1865. (114) Al-Tel, T. H.; Semreen, M. H.; Voelter, W. Org. Biomol. (145) Mahuteau-Betzer, F.; Ghosez, L. Tetrahedron 2002, 58, Chem. 2010, 8, 5375. 6991. (115) Christoffers, J.; Werner, T.; Frey, W.; Baro, A. Chem. Eur. (146) Gao, F. Y.; Burnell, D. J. J. Org. Chem. 2006, 71, 356. J. 2004, 10, 1042. (147) Coquerel, Y.; Greene, A. E.; Deprés, J.-P. Org. Lett. 2003, 5, (116) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931. 4453. (117) Cho, Y. S.; Carcache, D. A.; Tian, Y.; Li, Y.-M.; (148) Carret, S.; Deprés, J.-P. Angew. Chem. Int. Ed. 2007, 46, Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 14358. 6870. (118) Yan, B.; Spilling, C. D. J. Org. Chem. 2008, 73, 5385. (149) Varea, T.; Alcalde, A.; de Castillo, C. L.; de Arellano, C. R.; (119) Xu, Y.; McLaughlin, M.; Chen, C.-y.; Reamer, R. A.; Cossio, F. P.; Asensio, G. J. Org. Chem. 2012, 77, 6327. Dormer, P. G.; Davies, I. W. J. Org. Chem. 2009, 74, 5100. (150) (a) Geng, F.; Liu, J.; Paquette, L. A. Org. Lett. 2002, 4, 71. (120) Deng, G.; Xu, B.; Wang, J. Tetrahedron 2005, 61, 10811. (b) Paquette, L. A.; Geng, F. Org. Lett. 2002, 4, 4547. (121) Zhuo, X.; Xiang, K.; Zhang, F.-M.; Tu, Y.-Q. J. Org. Chem. (151) Grant, T. N.; West, F. G. J. Am. Chem. Soc. 2006, 128, 9348. 2011, 76, 6918. (152) Trost, B. M.; Xia, J.; Maulide, N. J. Am. Chem. Soc. 2008, (122) Piancatelli, G.; D’Auria, M.; D’Onofrio, F. Synthesis 1994, 130, 17258. 867. (153) Pujanauski, B. G.; Prasad, B. A. B.; Sarpong, R. J. Am. (123) Faza, O. N.; López, C. S.; Álvarez, R.; de Lera, Á. R. Chem. Chem. Soc. 2006, 128, 6787. Eur. J. 2004, 10, 4324. (154) Jung, M. E.; Davidov, P. Org. Lett. 2001, 3, 3025. (124) (a) Csákÿ, A. G.; Contreras, C.; Mba, M.; Plumet, J. Synlett (155) Matsuda, T.; Tsuboi, T.; Murakami, M. J. Am. Chem. Soc. 2002, 1451. (b) Csákÿ, A. G.; Mba, M.; Plumet, J. Synlett 2007, 129, 12596. 2003, 2092. (156) Mehta, G.; Umarye, J. D. Org. Lett. 2002, 4, 1063. (125) Harikrishna, M.; Mohan, H. R.; Dubey, P. K.; Subbaraju, G. (157) Iqbal, M.; Duffy, P.; Evans, P.; Cloughley, G.; Allan, B.; V. Synth. Commun. 2009, 39, 2763. Lledó, A.; Verdaguer, X.; Riera, A. Org. Biomol. Chem. (126) Ulbrich, K.; Kreitmeier, P.; Reiser, O. Synlett 2010, 2037. 2008, 6, 4649. (127) Yin, B.-L.; Wu, Y.-L.; Lai, J.-Q. Eur. J. Org. Chem. 2009, (158) Demuynck, A. L.W.; Levecque, P.; Kidane, A.; Gammon, 2695. D. W.; Sickle, E.; Jacobs, P. A.; De Vos, D. E.; Sels, B. F. (128) Veits, G. K.; Wenz, D. R.; Read de Alaniz, J. Angew. Chem. Adv. Synth. Catal. 2010, 352, 3419. Int. Ed. 2010, 49, 9484. (159) Shindo, M.; Sato, Y.; Shishido, K. J. Org. Chem. 2001, 66, (129) Reddy, B. V. S.; Narasimhulu, G.; Lakshumma, P. S.; 7818.

Reddy, Y. V.; Yadav, J. S. Tetrahedron Lett. 2012, 53, 1776. (160) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron Lett. 2002, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (130) Li, S.-W.; Batey, R. A. Chem. Commun. 2007, 3759. 43, 5039. (131) Wenz, D. R.; Read de Alaniz, J. Org. Lett. 2013, 15, 3250. (161) (a) Kuhn, C.; Skaltsounis, L.; Monneret, C.; Florent, J.-C. (132) Jung, M. E.; Yoo, D. J. Org. Chem. 2007, 72, 8565. Eur. J. Org. Chem. 2003, 2585. (b) Kuhn, C.; Roulland, E.; (133) (a) Nunes, J. P. M.; Veiros, L. F.; Vaz, P. D.; Afonso, C. A. Madelmont, J.-C.; Monneret, C.; Florent, J.-C. Org. Biomol. M.; Caddick, S. Tetrahedron 2011, 67, 2779. (b) Caddick, Chem. 2004, 2, 2028. S.; Cheung, S.; Doyle, V. E.; Frost, L. M.; Soscia, M. G.; (162) Ballini, R.; Boscia, G.; Fiorini, D.; Gil, M. V.; Petrini, M. Delisser, V. M.; Williams, M. R. V.; Etheridge, Z. E. Khan Org. Lett. 2001, 3, 1265. S.; Hitchcock, P. B.; Pairaudeau, G.; Vile, S. Tetrahedron (163) Pal, R.; Clark, R. J.; Manoharan, M.; Alabugin, I. V. J. Org. 2001, 57, 6295. Chem. 2010, 75, 8689. (164) Heck, M.-P.; Matt, C.; Wagner, A.; Toupet, L.; Mioskowski, C. Eur. J. Org. Chem. 2010, 966.