Recent Advances in Total Synthesis Via Metathesis Reactions

Home , Alkyne metathesis, Enyne metathesis, Grubbs catalyst, Total synthesis

SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2018, 50, 3749–3786 review 3749 en

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

Recent Advances in Total Synthesis via Metathesis Reactions

Iván Cheng-Sánchez Francisco Sarabia*

Department of Organic Chemistry, Faculty of Sciences, University of Málaga, Campus de Teatinos s/n. 29071- Málaga, Spain [email protected]

Received: 16.04.2018 ly explained by the emergence, design, and development of Accepted after revision: 30.05.2018 powerful catalysts that are capable of promoting striking Published online: 18.07.2018 DOI: 10.1055/s-0037-1610206; Art ID: ss-2018-z0262-r transformations in highly efficient and selective fashions. In fact, the ability of many of them to forge C–C bonds be- Abstract The metathesis reactions, in their various versions, have between or within highly functionalized and sensitive com- come a powerful and extremely valuable tool for the formation of car- pounds has allowed for the preparation of complex frame- bon–carbon bonds in organic synthesis. The plethora of available catalysts to perform these reactions, combined with the various works, whose access were previously hampered by the lim- transformations that can be accomplished, have positioned the me- itations of conventional synthetic methods. Among the tathesis processes as one of the most important reactions of this centu- myriad of recent catalysts, those developed and designed to ry. In this review, we highlight the most relevant synthetic contributions promote metathesis reactions have had a profound impact published between 2012 and early 2018 in the field of total synthesis, reflecting the state of the art of this chemistry and demonstrating the and created a real revolution in the field of total synthesis, significant synthetic potential of these methodologies. by virtue of their ability to promote a stunning number of 1 Introduction synthetic transformations, depending on the nature of the 2 Alkene Metathesis in Total Synthesis starting materials and reaction conditions. Metathesis reac- 2.1 Total Synthesis Based on a Ring-Closing-Metathesis Reaction tions1 include the alkene-, enyne-, and alkyne-metathesis 2.2 Total Synthesis Based on a Cross-Metathesis Reaction 2.3 Strategies for Selective and Efficient Metathesis Reactions of reactions, together with multiple variants of polyalkenic or Alkenes polyalkenynic systems as starting precursors involved in 2.3.1 Temporary Tethered Ring-Closing Metathesis cascade processes.2 Among these, the alkene metathesis re- 2.3.2 Relay Ring-Closing Metathesis action (Scheme 1, A), in which cyclic olefins or linear 2.3.3 Stereoselective Alkene Metathesis alkenes are formed through ring-closing metathesis (RCM), 2.3.4 Alkene Metathesis in Tandem Reactions 3 Enyne Metathesis in Total Synthesis cross-metathesis (CM) process, or their different guises 3.1 Total Syntheses Based on a Ring-Closing Enyne-Metathesis Reac- (stereoselective, rearrangement, tethered or relay ring-clos- tion ing metatheses), is the most extensively employed. Indeed, 3.2 Total Syntheses Based on an Enyne Cross-Metathesis Reaction these transformations occupy a privileged position in mod-

3.3 Enyne Metathesis in Tandem Reactions This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ern organic synthesis. Less frequently used, but no less im- 4 Alkyne Metathesis in Total Synthesis 4.1 Total Synthesis Based on a Ring-Closing Alkyne-Metathesis Reac- portant, are the enyne and alkyne metatheses (Scheme 1, B tion and C), which have also become valuable synthetic reac- 4.2 Other Types of Alkyne-Metathesis Reactions tions with additional advantages over alkene metatheses. 5 Conclusions Such is the case of enyne metathesis involved in cascade Key words alkene metathesis, alkyne metathesis, enyne metathesis, processes, or the case of alkyne metathesis owing to the natural products, total synthesis versatility of the alkyne group by allowing for further transformations, thus considerably expanding the structural diversity of the products that can be formed. 1 Introduction Certainly, behind the success of all these processes are the unique catalysts themselves that enable these transfor- The outstanding and impressive level that organic syn- mations. Since the discovery of the first well-defined tung- thesis has reached in the last few decades, especially in the sten carbene catalyst by Katz3 and the elucidation of the field of the total synthesis of natural products, can be large- mechanism of alkene metathesis by Chauvin4 in the 1970s,

Syn thesis I. Cheng-Sánchez, F. Sarabia Review key innovations were the Schrock catalyst 1 in 19905 and more detail later in the alkyne metathesis section. Together the discovery of the ruthenium-based catalyst 2 by Grubbs with the prominent activity and stability of the aforemen- in 1993.6 These discoveries marked the beginning of an ex- tioned catalysts, another feature that has been improved in traordinary and burgeoning race towards more efficient the evolution of catalyst design27 is the exceptional func- catalysts in terms of activity, stability, and functional group tional group tolerance that all these catalysts display, which tolerance, represented by the ruthenium species 3–147–18 in turn has positioned them as one of the most powerful (Figure 1). synthetic tools in modern organic synthesis. Consequently, These highly efficient catalysts are representative mem- total synthesis has enormously benefitted from the metath- bers of three generations of ruthenium complexes, in which esis reactions, as demonstrated by the extensive use of the introduction of an N-heterocyclic carbene (NHC) ligand these reactions in their intramolecular and intermolecular (see 4, 6–14) resulted in an increase in the catalytic activity versions. In fact, the flurry of contributions, in which the and thermal stability of the catalysts. The catalysts, devel- metathesis reaction represents either the key step for the oped between 1996–2007, gave rise to the rational design successful completion of a synthesis or a useful and effi- of new catalysts to enable both stereoselective and stereo- cient synthetic tool employed along the synthetic course, is retentive metathesis processes, leading to the molybde- a growing component of the organic chemistry literature. num, tungsten, and ruthenium carbene complexes 15–27, Given the relevance and impact of this reaction in the among others.19–22 Additions to this armory of valuable cat- field of organic chemistry, a large number of reviews, alysts, are the water-soluble catalysts in form of PEGylated books, and book chapters have been devoted to all aspects complexes23 or ruthenium-based catalysts supported on ac- of these reactions. Among all the excellent reviews focused tivated surfaces,24 which expand even further the scope and on the applications of metathesis reactions in natural prod- applications of the chemistry, particularly in regards to ad- ucts synthesis,28 some key contributions by Nicolaou dressing environmental concerns.25 All these catalysts are (2005),29 Pérez-Castells (2006),30 and Prunet (2011)31 are appropriate for alkene and enyne metatheses.26 Interesting- notable. A review published in 2017 by Vanderwal32 is ly, for the latter case, the process can be also effected by noteworthy, wherein the most relevant contributions in the other transition-metal-based catalysts such as those based field of the last years were highlighted, but in a very generic on Pt, Pd, or Ir via a completely different mechanism. A sep- form. On the other hand, an excellent book was published arate case is the alkyne-metathesis reaction, which despite dealing with metathesis reactions in the synthesis of natu- the mechanistic similarity with alkene metathesis, requires ral products, covering all the aspects of these reactions in a different type of catalyst. Indeed, in this case, the variety the field of total synthesis up to 2010.33 In addition, numer- of catalysts available is not as great as those developed for ous reviews have been published on very specific items, the alkene metathesis reactions, as will be discussed in dealing with a particular type of metathesis reaction or a

Biographical Sketches

Iván Cheng Sánchez was 2015 he started his Ph.D. stud- modomain inhibitors for cancer born in Málaga (Spain) in 1992. ies under the guidance of Prof. treatment. His current research He received his B.Sc. in chemis- F. Sarabia. In 2017 he joined the focuses on total synthesis of try in 2014 and his M.Sc. in laboratories of Prof. C. Nevado natural products and design chemistry in 2015 from Málaga at University of Zurich for a and synthesis of new bioactive University, after conducting re- short research stay of 3 months agents inspired by natural prod-

search in the laboratories of where he was involved in the ucts through novel asymmetric This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Prof. F. Sarabia. In November synthesis of novel ATAD2 bro- methodologies.

Francisco Sarabia received his to Full Professor in 2011. Prof. new synthetic methodologies Ph.D. degree from University of Sarabia has been visiting profes- and medicinal chemistry, and Málaga (Spain) in 1994 under sor in the Technological Insti- the discovery of new bioactive the supervision of Prof. López- tute of Zürich (ETH) in 1998 compounds. He is the chairman Herrera. After postdoctoral re- with Prof. A. Vasella, The Scripps of the Department of Organic search with Prof. K. C. Nicolaou Research Institute in 2001 with Chemistry since 2014 and sci- at the Scripps Research Institute Prof. Nicolaou, and Scripps Flor- entific responsible of the NMR in La Jolla (1995–1997), he re- ida in 2013 with Prof. W. R. facilities of the University of turned to the University of Roush. His research interests in- Málaga. Málaga in 1998 as Assistant Pro- clude the total synthesis of nat- fessor, where he was promoted ural products, development of

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

A) Alkene-Metathesis Reactions 2 Alkene Metathesis in Total Synthesis

RCM 2.1 Total Syntheses Based on a Ring-Closing- n n Metathesis Reaction R E-selective CM R' The ring-closing metathesis (RCM) reaction is one of the R CM R + R' R' most frequently employed methodologies to construct cy- R' clic systems, becoming a common synthetic tool in the R Z-selective CM modern organic synthetic laboratory. Indeed, a practically limitless array of carbocyclic or R Stereoselective RCM heterocyclic ring systems, including small-, medium-, and n large-sized rings, can be constructed utilizing this transfor- X R X R n mation. In the context of total synthesis, the preparation of small- and medium-sized rings usually plays a complemen-

ROM/RCM tary role implemented along the synthetic path. However, n n R X (Ring-rearrangement R X in the case of macrocyclic systems, the RCM reaction com- metatheses) (X = CH2 or monly constitutes a crucial step for the completion of the heteroatom) synthesis. For this reason, in this section, we would like to highlight representative examples reported in the last few RCM years in which the RCM reaction was the key step. As a first (Tethered Ring– series of examples in this category, it is worth mentioning Closing Metathesis) X X the polyketide-type compounds ripostatin B (28)35 and A 36 37 38 X (29), FD-895 (30), cruentaren A (31), pikromycin 39 40 41 X (32), zampanolide (33), amphidinolide G (34), palmerolide A (35),42 ecklonialactone B (36),43 gambieric acid A (37),44 nominal gobienine A (38),45 trienomycin A (39) and F RRCM (40),46 13-demethyllyngbyasolide B (41),47 incednam (42),48 (Relay Ring– Closing Metathesis) sekothrixide (43),49 aspicillin (44),50 macrolide fragment of (X = CH2 or heteroatom) FD-891 (45),51 carolacton (46)52 (Figure 2), cytospolide P (47),53 pectenotoxin (48),54 Sch725674 (49),55 aspergillide B B) Enyne-Metathesis Reactions (revised structure, 50),56 iriometolide 3a (51),57 paecilomy- Enyne RCM Enyne RCM cin B (52),58 fidaxomicin (53),59 exiguolide (54),60 neo- [For macrocycles] [For small and peltolide (55),61 methynolide (56),62 and iriomoteolide-2a n+1 n medium-sized rings] n (57)63 (Figure 3). In addition, the group of alkaloids and cy- C) Alkyne-Metathesis Reactions clodepsipeptides are illustrated with the examples of man- 64 65 66 RCAM zamine A (58), isoschizogamine (59), vertine (60), haliclamide (61),67 5-epi-torrubiellutin (62),68 petrosin (63),69 n n the YM-254890 analogue 64,70 nannocystin A (65) and A0 CAM 71 72 73 R + R' R R' (66), nakadomarin A (67), marineosin A (68), kana- 74 75 Scheme 1 Metathesis reactions in organic synthesis mienamide (69), and 15-epi-aetheramide A (70) (Figure

4). This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Finally, among the total syntheses of terpenes that em- particular kind of natural products.34 In light of this publi- ploy the RCM reaction, particularly noteworthy are the syn- cation landscape, the current review intends to cover the theses of 17-deoxyprovidencin (71),76 uprolide G acetate recent advances reported in the field of total synthesis, in (72),77 terreumol C (73),78 pavidolide B (74),79 and boscartin which a metathesis reaction has been essential for the com- F (75)80 (Figure 5). As an indication of the effectiveness of pletion of the synthesis, for the period 2012 to early 2018, the RCM processes, the yields achieved in many cases were with particular emphasis on recent pioneering contribu- reasonable to excellent (44–99% yields), with some exceptions, as well as exciting applications in the context of total tions with lower yields (17–34%), and in general excellent synthesis. With this review, we are confident that we will stereoselectivities, with some exceptions [ecklonialactone B provide an updated state of the art of this field and will fur- (36),43 fidaxomicin (53),59 iriomoteolide-2a (57),63 na- ther demonstrate the power that this chemistry has to offer kadomarin A (67)72], for which the isomeric ratios are indi- and the prospects that it provides for the future. cated.

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

PCy N N N N i i 3 Mes Mes Mes Mes Pr Pr PCy3 PCy3 N N PCy Mes Mes Cl 3 F C N Me Cl Cl Ru Cl Cl Ph 3 O Cl Ru Ru Cl Mo Ph Ru Ph Ru Ru F C Ph Ru Cl 3 Me Me O Cl Cl Cl Ph Cl Ph O O Cl O PCy PCy Cl Me PCy3 3 3 PCy Me Me CF 3 Me Me 3 Me Me Ph CF3 1 2 3 (Grubbs I) 4 (Grubbs II) 5 (H-G I) 6 (H-G II) 7 8 [Schrock, 1990]5 [Grubbs, 1993]6 [Grubbs, 1995]7 [Grubbs, 1999]8 [Hoveyda, 1998]9 [Hoveyda, 2000]10 [Blechert, 2002]11 [Fürstner, 1999]12

Me Mes N N Mes N N N N N N N N Mes Mes Mes Mes Mes Mes Cl Cl Ph N Ru Cl Cl Cl Me Ru Ru Ru Ru Ph Cl Br Cl Cl Cl Cl N PCy3 O NO2 O SO2NMe2 O Me Me Me Br Me Me Me 9 10 11 12 13 (C884) [Nolan, 1999]13 [Grela, 2002]14 [Zhan, 2007]15 [Grubbs-Stewart, 2007]16 [Grubbs, 2002]17 F F Et3SiO F F i i N N CF3 Pr Pr Mes Mes F F N N Me N Me N Me Ph N N O Cl Mo Mo Ph Mo Ph N Me Ru Me Ph Br Me Me Br Mo Cl O Br O X O Me N Br Br X F O Me TBSO TBSO TBSO F Et3SiO MeO N O Me 17: X = Cl 18: X = Br 14 15 16 19: X = I 20 [Williams, 2016]18 [Schrock, Hoveyda, 2008]19 [Schrock, Hoveyda, 2008]19 [Schrock, Hoveyda, 2008]19 [Schrock, Hoveyda, 2008]19

iPr iPr iPr Cl Cl N N Mes N N Mes Mes N N Mes N N N X F N i W tBu W Pr S F S i O Pr i Ru Ru Ru i Pr Br O N Pr O iPr O O S F S Br O O TBSO O X F Me Me Me iPr i Pr Me Me Me 24: X = H 27 21 22 23 25: X = Cl 26: X = Br [Schrock, 2009]20 [Schrock, 2009]20 [Grubbs, 2013]21 [Hoveyda, 2013]22 Figure 1 Common catalysts used for alkene- and enyne-metathesis reactions: evolution of their design and development

In addition to the previous contributions, we can find in force the isomerization by subsequent treatment of the the literature other cases that deserve a more detailed de- RCM product with RuH(PPh3)3(CO)Cl, which then afforded

scription. A first example is the synthesis by Brimble and the natural product 76 in a good overall yield. This synthet- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. co-workers of palmyrolide A (76) (Scheme 2),81 a macrolide ic study constituted the first reported isomerization of an isolated from Leptotyngbya cf. sp. and Oscillatoria sp. that N-allylated tertiary amide in a macrocyclic setting and, fur- displays interesting neuroprotective properties, combined thermore, allowed the revision of the structure of the natu- with low cytotoxicity. The synthesis was initially based on a ral product, which was erroneously assigned to the initial RCM reaction of a starting enamide precursor; however, proposed structures 79 and 80 (Scheme 2). this RCM attempt failed despite screening of a wide variety A second relevant example is from Carreira and co- of reaction conditions. As a consequence of these disap- workers, who in a stereodivergent-oriented approach, de- pointing results, they considered a sequential RCM/olefin scribed the synthesis of the four diastereomers of Δ9-tetra- isomerization from the diolefin 77, with the possibility that hydrocannabinol (81) via a RCM reaction from the acyclic the desired isomerization may occur in the presence of the precursors 82 (Scheme 3).82 Interestingly, the four stereo- corresponding Grubbs catalyst. However, despite the RCM isomers of 82 were efficiently prepared by an elegant and reaction of diolefin 77 proceeding efficiently when treated novel dual catalytic process based on the use of a set of two with the Grubbs II catalyst (4) to give macrocycle 78, the chiral catalysts [Ir/(P, olefin) and a secondary amine] for the isomerization was not observed. This result led them to enantioselective allylation of 5-methylhex-5-enal. The RCM

Syn thesis I. Cheng-Sánchez, F. Sarabia Review reaction of each stereoisomer of 82 was achieved under system. Despite this potential difficulty, the RCM reaction very mild conditions (25 °C) with the Grubbs II catalyst (4) has proven to be highly efficient in many cases. An instruc- to provide the corresponding THC precursors 83 in excel- tive example of this is demonstrated in the synthesis of the lent 85–92% yields, which were transformed into the final polycyclic xanthone-type antibiotic IB-00208 (84), report- products in three additional steps (Scheme 3). Previous ed by Martin and co-workers (Scheme 4).84 Thus, the syn- syntheses of Δ9-THC 81 and related cannabinoid-type com- thesis of the key cyclobutenone 86 was successfully pounds have also employed the RCM reaction to construct achieved via a RCM reaction of precursor 85 when subject- the cyclohexene ring containing in these intriguing natural ed to the Grubbs II catalyst (4). The resulting cyclobutenone products.83 was rearranged to the desired xanthone 87 under thermal The construction of medium-sized rings containing cy- conditions and represents a general route to construct clobutanes represents a challenging ring-closing metathesis polycyclic benzoquinones. A few more steps then converted due to the highly strained character of the resulting bicyclic the xanthone 87 into the targeted natural product 84.

Me RCM Me RCM Me Me Me Me RCM O (77%)[35a] (84%) (44%) Me (64%)[35b] OMe OH O O OAc HO O O(48%)[35c] O O O

O OH O OH FD-895 (30) OH OH Me Me (Burkart, 2012)[37] OH OH Ripostatin B (28) Ripostatin A (29) Me (Altmann, 2012)[35a] (Prusov, 2012)[36] Me OH O [35b] (Christmann, 2012) O O Me Me OH (Prusov, 2012)[35c] RCM (84%) O OH Me Me HO Me O O HO HO N OH Me OH O Me H O Me Me Me Me Me Me RCM OH O NH Me O O NMe O (65%) O 2 Me Me Me OH O RCM O O O (95%) O MeO Me Amphidinolide G (34) RCM [41] Pikromycin (32) Zampanolide (33) (Nishiyama, 2012) (79%) [39] HO Me (Kang, 2012) (Ghosh, 2012)[40] (quant.) Cruentaren A (31) Me O RCM (Blagg, 2012)[38] H Me H Me Me H H O O H O O RCM and O Me OH HO O epoxidation O O H H H HO O O H H Me N RCM H H H O H (93%; E/Z = 2:1) Me H H O Me O Me Me (–)-Ecklonialactone B (36) H Me OH [43] O H (Hiersemann, 2013) H Me O HO Gambieric Acid A (37) Me O HO C Me H RCM 2 [44] Me Palmerolide A (35) (62%) (Fuwa, Sasaki, 2012) (Prasad, 2012)[42] O NH2 OH OMe OH OH RCM(17%) OH MeO OH HO HO Me O OH NH Me O O O Me Me HO O HO O HO HN Me O O O Me HO Me Me O O OMe O H Me Me X N Me OMe This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. RCM and O hydrogenation RCM RCM and Incednam (42) O O Me (21%) hydrogenation (83%) Br OH (Toshima, O (81%) (+)-Trienomycin A (39): X = cyclohexyl 2013)[48] (–)-13-demethyllyngbyaloside B (41) (+)-Trienomycin F (40): X = (E)-but-2-enyl (Fuwa, 2013)[47] Nominal Gobienine A (38) (Krische, 2013)[46] [45] (Fürstner, 2013) OH OH Me Me Me RCM OH (74%) RCM Me Me O HO O OH (55%) OH b Me Me O OH O O Me OH OH OH RCM and O O O OMe Me Me hydrogenation CO2H O (62%) OH Me (+)-Aspicilin (44) a Me Me Me Me Me Me Me RCM O O (Shaw, 2014)[50] (60%) RCM and Carolacton (46) Sekothrixide (43) hydrogenation Macrolactone Fragment a(Phillips, 2014)[52a] (Nagumo, 2014)[49] [52a] of FD-891 (45) (76%) b(Goswami, 2017)[52b] [52b] (Kanoh, 2014)[51] (74%) Figure 2 Selected macrocyclic polyketides synthesized via a RCM reaction (yields refer only to the RCM reaction)

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

Me O Me O OAc O RCM and O O H O hydrogenation Me Me O H OH O OH OH O (65%) O OH Me H OH Me O Me O O HO O O RCM H H [55a] O Me Me (36%) O RCM Me OH RCM (70%)[55b] (82%) Cytospolide P (47) (64%) Pectenotoxin-2 (48) O O HO (Goswami, 2014)[53] (Fujiwara, 2014)[54] C5H11 Revised Aspergillide B (50) Me (Mohapatra, 2014)[56] RCM (66%) Sch725674 (49) HO RCM O OH OH Me (Prasad, 2014)[55a] O (81%) Me O (Kumar, 2016)[55b] HO HO Cl O (75%; E/Z = 2:1)RCM O O O HO OMe O OH OH O O Et H OH OMe Et Cl HO OH Me O Me HO Me O Iriomoteolide 3a (51) O MeH H Paecilomycin B (52) O H O [57] Me HO O (Prasad, 2014) [58] OH Fidaxomicin (53) (Ohba, 2015) Me Me [59] Me Me (Gademann, 2015)

Me Me OMe O Me MeO C RCM (98%) Me HO 2 O O Me HO MeO Me Me O O Me O Me Me HN O OH OH RCM RCM and (78%) hydrogenation Me Me O Me O O O O O (89%; Z/E = 98:2) Methynolide (56) Me O [62] O O Me N (Kobayashi, 2017) HO O O Neopeltolide (55) RCM (87%; E/Z = 5:1) (Hoveyda, 2015)[61] MeO2C Iriomoteolide-2a (57) [63] (–)-Exiguolide (54) (Fuwa, 2018) (Song, 2015)[60] Figure 3 Selected macrocyclic polyketides synthesized via a RCM reaction (yields refer only to the RCM reaction)

Me O O OMe * N a) Grubbs II (4) N * CHO a) Grubbs II (4) OMe Me O CH Cl , reflux Me O CH2Cl2, 25 °C * Me 2 2 Me * C5H11 OMe O O 92% for (S,S)-83 CHO C H OMe Me Me Me 87% for (R,S)-83 5 11 Me Me (S,S)-82 90% for (S,R)-83 (S,S)-83 Me Me Me Me (R,S)-82 85% for (R,R)-83 (R,S)-83 77 78 (S,R)-82 (S,R)-83 (R,R)-82 (R,R)-83 b) RuH(PPh3)3(CO)Cl (64% over toluene, reflux 2 steps) b) Pinnick oxidation c) Me3SiCHN2 Initially proposed structures of Palmyrolide A d) MeMgI, 0 °C to 160 °C, O O O 1 atm to 0.2 atm then ZnBr2 N N N Me O Me O Me O R = C H Me Me Me 5 11 O O O Me Me Me Me Me Me Me

Me Me Me This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. HO HO HO HO Me Me Me Me Me Me H H H H 79 80 Palmyrolide A (76) H H H H Me Me R O R O Me R O Me R O Scheme 2 Total synthesis of palmyrolide A Me Me Me Me (S,S)-81 (R,S)-81 (S,R)-81: (R,R)-81: (–)-Δ9-cis-THC (–)-Δ9-trans-THC

9 As another example of the use of the RCM reaction to Scheme 3 Total synthesis of Δ -THC and its stereoisomers fashion cyclobutane-containing polycyclic systems, we highlight the total synthesis of the cytotoxic meroterpenoid an excellent 90% yield by the action of Crabtree’s catalyst, psiguadial B (88) by Reisman and co-workers (Scheme 5),85 the resulting product 91 was carried towards the natural in which the RCM reaction of diolefinic cyclobutane 89, car- product in four additional steps. ried out with the H-G II catalyst (6) in the presence of 1,4- A stunning example of the power of the RCM reaction benzoquinone, afforded in an excellent 93% yield the corre- can be found in the construction of strained ring systems sponding tricyclic derivative 90. After a formidable chemo- via a transannular process as applied in the recent synthesis selective hydrogenation of 90, which was accomplished in of the cembranolides sarcophytonolide H (92) and isosarco-

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

RCM RCM OH Me Me O RCM and (97%) (37%) O hydrogenation O O O N N N (49%) OAc N O H Me Me H H N 1 5 H HO O Me N Me OH OH N O N N Me O Me Me MeO MeO O RCM (93%) N RCM OMe OMe (73%) 5-epi-Torrubiellutin (62) Isoschizogamine (59) Vertine (60) [68] Haliclamide (61) (Chandrasekhar, 2013) (Fukuyama, 2012)[65] (Kündig, 2012)[66] Manzamine A (58) (Altmann, 2013)[67] RCM (80%; (Dixon, 2012)[64] O RCM (79%) Z/E = 60:40) Me O H N Me Me N H Me NH O O OMe O O N H O H Me O H NH O N O O O RCM and O O H hydrogenation Me O Me Me HO NH Me O RCM (89%) N Me RCM HO (93%) Me N N (81%) H O H Me Me Me Nakadomarin A (67) O X O WU-07047 (64), a YM-254890 analogue Me (Clark, 2016)[72] H Me N (Moeller, 2015)[70] OMe Me HO HO (+)-Petrosin (63) Y (Tokuyama, 2014)[69] Me Nannocystin A (65): X = Y = Cl O Nannocystin A0 (66): X = Y = H O O Me O N OMe (Wang, 2016)[71] O Me Me NH Me N Me O NH Me Me O 11 N Me Me N O 1 O Me N RCM and O O H 15 hydrogenation Me Me Me OMe RCM and (67%) hydrogenation OH Me Kanamienamide (69) RCM (34%) (52%) [74] Marineosin A (68) (He, 2017) (+)-15-epi-Aetheramide A (70) [73] (Shi, 2016) (Prasad, 2017)[75] Figure 4 Selected alkaloids and cyclodepsipeptides synthesized via a RCM reaction (yields refer only to the RCM reaction)

phytonolide D (93) by Takamura and co-workers (Scheme RCM and O Me OH O OMe H 86 epoxidation OMe O 6). These natural products, isolated from the soft coral of (76%) H Me HO O H Me the genus Sarcophyton, exhibit potent antifouling activities O H H MeO O against the larval settlement of barnacle Balanus amphirite Me O OH O Me Me O with EC50 values in the low μg/mL range. In these syntheses, O RCM O OAc RCM and Me the construction of the butenolide contained in the macro- O (82%) O hydrogenation Me cyclic framework, which is a structural feature of this class (75%) 17-Deoxyprovidencin (71) Uprolide G acetate (72) (–)-Terreumol C (73) of diterpenes, was achieved via a RCM reaction of the corre- (Mulzer, 2014)[76] (Tong, 2015)[77] (Lindel, 2016)[78] sponding precursors 94 and 96 by treatment with the H-G RCM and isomerization Me II catalyst (6) in toluene at 100 °C. The efficiency of these Me H O (85%) processes is quite remarkable, given both the steric encum- Me O Me H O brance around the ring-closure site and the complexity of This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Me HO O RCM and O H epoxidaton the system. The completion of the synthesis of both natural H H Me Me O Me (55%) products was carried out in three additional steps from the O Me RCM products. Pavidolide B (74) Boscartin F (75) (Yang, 2017)[79] (Sugita, 2018)[80] Further evidence for the utility of the RCM reaction in the construction of sterically crowded and highly function- Figure 5 Selected terpenes synthesized via a RCM reaction (yields refer only to the RCM reaction) alized ring systems is provided by the recent total synthesis of the highly oxidized diterpenoids ryanodol (97) and related diterpenes, natural products that display powerful phar- yield over four steps, to obtain advanced precursor 100. Re- macological and insecticidal activities via their interactions markably, once again, the presence of unprotected func- with the ryanodine receptors.87 The synthesis of the C-ring tionalities was well tolerated under these ruthenium-cata- of ryanodol was undertaken by Inoue and co-workers via lyzed reaction conditions, thus underscoring the mildness the RCM reaction of the precursor 99 (Scheme 7),88 pre- and efficiency of these reactions in a complex setting. From pared from the allylic diketone 98 in three steps, in 58%

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

Me O Me O O O PMBO PMBO O O OMOM OMOM a) H-G II (6) Me toluene, 100 °C Me OMe Grubbs II (4), PhMe OMe Me Me MOMO OMe MOMO OMe b) HCl, i-PrOH (81%) Me Me (52% over 2 steps) O O Me OMOM Me OH 85 86 94 95 (6 steps) O HO Me O O O c) AcCl, pyridine OH Me O OMe Me d) DDQ, CH2Cl2/pH 7 buffer O O OMe Me OMOM Me (77% over 2 steps) O O O OMe O OAc Me Me O MOMO Sarcophytonolide H (92) OMe O OMe O O MeO TBSO O OMe O OMe PMBO O O IB-00208 (84) 87 a) AcCl, pyridine Me b) H-G II (6), toluene, 100 °C Me Me Me Scheme 4 Total synthesis of IB-00208 Me c) DDQ, CH2Cl2/pH 7 buffer Me d) TPAP, NMO Me OH Me OAc (8% over 4 steps) 96 Isosarcophytonolide D (93) Me Me H Me Me H Scheme 6 Total synthesis of sarcophytonolide H and isosarcophytono- Me OH H OH lide D a) H-G II (6) Me 1,4-BQ, PhH, 80 °C MeO Br (93%) MeO Br This stereochemical outcome was likely influenced by the presence of the amide group in the starting precursor, 89 OMe 90 OMe which could coordinate with the transition metal resulting b) H2, Crabtree's cat. (90%) in a consequent reduction of the catalytic activity. In light

Me H Me H of these results, an exploration of other chiral catalysts led Me Me CHO to the observation that as the size of the halide substituent H O OH (4 steps) H OH on the complex increased, the level of enantioselectivity Me Me was improved, with a (–)-103/(+)-103 93:7 ratio of enantio- CHO H Ph OH MeO Br mers being achieved when the diiodo complex 19 was em- (+)-Psiguadial B (88) ployed. As the natural product possessed the opposite con- 91 figuration, this result was extended to the enantiomer cata- OMe lyst ent-19 to obtain the product 103 with the configuration Scheme 5 Total synthesis of psiguadial B of the natural product in 92% yield and with an enantio- meric ratio of (+)-103/(–)-103 94:6. With the key product compound 100, the completion of the synthesis of ryanodol (+)-103 in hand, the synthetic route to the natural product (97) was accomplished in ten additional steps with mini- was delineated through the pentacyclic derivative 104, mal difficulty. which was prepared in an efficient manner from (+)-103 Within the stereoselective RCM processes, the use of according to the steps indicated in Scheme 8. From penta- chiral catalysts, such as the catalysts 15–22 designed by cycle 104, seven additional steps were required for comple-

Hoveyda, Schrock, and co-workers (see Figure 1), allows for tion of the synthesis of deoxoapodine (101). This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. the preparation of enantiomerically enriched products.89 OBn OBn Their applications and level of enantioselective control is Me Me O OMOM Me O OH nicely illustrated in the synthesis of the alkaloid deoxoapo- a) PdCl2(MeCN)2 Me b) BF ·OEt , Me S dine (101), a member of a family of alkaloids that share the H 3 2 2 H O O O pentacyclic aspidosperma core. This asymmetric synthesis Me O c) Me Me O d) H-G II (6) O HO O toluene, 80 °C was devised by Movassaghi and co-workers based on a de- 98 Li 99 (58% over Me Me symmetrization process of the achiral triolefin 102 Me Me 4 steps) OH OBn 90 Me (Scheme 8). Thus, achiral compound 102 was subjected to Me Me O Me (10 steps) O OMOM the catalytic activity of the chiral molybdenum pyrrolide HO E OH Me A H complex 17, which proved to be efficient in terms of chemi- C B OH Me O Me O H Me cal yield and stereoselectivity in the synthesis of quebra- H O HO O HO O chamine,19c however, in this case, the catalyst offered only H (+)-Ryanodol (97) Me 100 moderate enantioselectivity [er (–)-103/(+)-103 82:18]. Me Scheme 7 Total synthesis of ryanodol

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

moderate yields, together with degradation products. They explored structural modifications of the precursor, by in- N O a) ent-Mo-MAP (ent-19) N O C6H6, 22 °C creasing its reactivity by removing the ester group, together (92%; er = 94:6) with a complete optimization study of the RCM reaction. N Mo-MAP (17): 95% (er = 82:18) N This extensive study led them to define a set of suitable Mo-MAP (18): 95% (er = 91:9) PMB PMB Mo-MAP (19): 98% (er = 93:7) structural requisites and reaction conditions to enable the 102 (+)–103 b) Pd(OAc)2, HClO4; targeted product. Accordingly, having established 109 as a then NaBH 4 (56% over suitable precursor, when this compound was treated with c) p-NO2C6H4COCl 4 steps) d) Bu3SnH, Tf2O H-G II catalyst (6) in toluene at 100 °C, the desired metathe- e) NaBH(OMe) 3 sis product 110 was obtained in 90% yield albeit as an in- N O (7 steps) N separable mixture of cis/trans isomers in 7:10 ratio. After OR transformation of the diastereomeric mixture 110 into the

N CO2Me reduced product 111, the isomers could be separated, and H N H PMB then the required cis isomer was taken forward to comple- (–)-Deoxoapodine (101) 104: R = p-nitrobenzoyl tion of the natural product in three more steps. Scheme 8 Total synthesis of deoxoapodine A noteworthy case in point is the natural product sora-

phen A1α (112), whose biological activities, including anti- Despite the excellent functional group tolerance and the microbial, antifungus, antidiabetes, and, more recently, an- low sensitivity to steric hindrances displayed by these cata- ticancer properties, has prompted great interest in chemi- lysts, we can find in the literature numerous examples in cal and biological circles. Preliminary synthetic efforts which steric factors appear to play a crucial role in unsuc- conducted by Ciufolini and co-workers,92 towards this com- cessful ring-closure reactions. This is the case for compound based on RCM were met with failure when they at- pound 105, which was devised as a potential precursor for tempted to effect a ring closure with various acyclic precur- the synthesis of the natural product pseudotabersonine sors 113–116, different catalysts and several reaction con- (106) by Martin and co-workers (Scheme 9).91 Thus, when ditions to obtain the corresponding coveted macrocycles 105 was treated with different ruthenium catalysts, includ- 117–120 (Scheme 10). Reasoning that steric factors were ing Grubbs I (3), Grubbs II (4), H-G II (6), or even the responsible for the failed RCM reactions, other investigators Grubbs–Stewart catalyst (12), which is especially reactive attempted the metathesis macrocyclization at less sterically towards sterically hindered olefins, the desired product encumbered sites. To this aim, Kalesse and co-workers93 ex- 107, resulting from a double RCM process was not ob- plored the RCM reaction of precursor 121 by treatment served, instead obtaining the monocyclized product 108 in with different ruthenium-based catalysts, however the results were similarly unfruitful in all cases (Scheme 10). In contrast to all these discouraging results, the RCM reaction TBSO TBSO TBSO Different of the desmethoxy precursor 123, explored by Micalizio N catalysts N N and co-workers (Scheme 10),94 provided in high yield (90%) the corresponding macrocycle 124 with Grubbs II catalyst N N N (4), proof that steric factors were responsible for the previ- PhO2S PhO2S CO Me PhO2S CO Me CO2Me 2 2 ous failures. From compound 124, they completed the syn- 105 107 108 thesis of the soraphen analogue 125. Interestingly, this so-

TBSO Et TBSO TBSO raphen analogue displayed promising cytotoxic activities

Et Et against B-lymphoma cell lines, revealing that the methoxy This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. N H-G II (6) N N H H toluene, 100 °C group present in the natural product was not essential for + (90%; dr = 7:10) H H biological activity. N N N A paradigmatic example in which the RCM reaction PhO2S PhO2S PhO2S 109 cis-110 trans-110 proved to be completely useless was in the synthesis of the bryostatins. The well-known fascinating synthesis of the (2 steps) bryostatins by Trost and co-workers was preceded by an

HO HO initial attempt of its total synthesis via a RCM reaction of the diolefins 126 and 127 (Scheme 11).95 However, after ex- Et Et Et N N N (3 steps) H H tensive screening of different catalysts and conditions, they + H H H H were unable to obtain the corresponding macrocycles 128 N N N H and 129. Furthermore, the implementation of the relay PhO S PhO S CO2Me 2 2 Pseudotabersonine (106) cis-111 trans-111 RCM (RRCM) strategy, as we will describe later, did not provide the expected macrocyclic olefin, when the RRCM pre- Scheme 9 Total synthesis of pseudotabersonine

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

Me Me MeO Me MeO Me MeO Me MeO Me TIPSO O TIPSO O OAc OAc Different MeO2C MeO2C catalysts RO X O RO X O O O O O Me OMe Me OMe OR1 OR1 O Different catalysts O Me Me OH H OH H OMe OMe Me O O Me O O 113: X = H, OH; R = MEM 117: X = H, OH; R = MEM Me Me 114: X = H, OH; R = TBS 118: X = H, OH; R = TBS AcO Me OR2 AcO Me OR2 115: X = H, OTES; R = TBS 119: X = H, OTES; R = TBS 116: X = O; R = TBS 120: X = O; R = TBS CO2Me CO2Me 126: R1 = TBDPS; R2 = TES 128: R1 = TBDPS; R2 = TES MeO Me MeO Me 127: R1 = R2 = H 129: R1 = R2 = H TBSO O Different TBSO O Me Me catalysts MeO Me MeO Me TBSO OH O TBSO OH O OAc OAc Me OMe Me OMe MeO2C MeO2C O O O O Me Me OTES OTES OMe OMe O Different O catalysts 121 122 OH H OH H Me O O O O (80%; 1:1 Z/E) Me Me MeO Me MeO Me AcO Me OTES AcO Me OTES TBSO O TBSO O a) Grubbs II (4) CO2Me CO2Me PMBO O O PMBO O O OMe Me OMe 130 131 Me (90%) Me Me Me Me Me MeO MeO Me OBn OBn 123 124 b) DDQ (46% over O O Grubbs II (4) O O c) TBAF 2 steps) OSEM OSEM O (17%) O Me MeO Me OMe H OH MeO O O OMe H HO O OH O O HO O O O Me OMe O O H Me OMe 132 133 H Me Me Scheme 11 Synthetic studies on bryostatins via RCM reactions OMe C11-Desmethoxy Soraphen A1α (112) Soraphen A1α (125)

Scheme 10 Synthetic attempts towards soraphen A1α via RCM and synthesis of the C11-desmethoxy analogue regio- and stereocontrolled construction of the medium- ring oxacycle that characterize these appealing natural products.98 Furthermore, for the chlorofucins 134 and 135 cursor 130 was subjected to different ruthenium-based cat- and bromofucins 136 and 137, their absolute configura- alysts, providing instead the macrocyclic product 131 as a tions were not established so their asymmetric syntheses result of the incorporation of the extended olefin onto the could unambiguously confirm their proposed configura- final cyclization product. Having ascribed the importance tions. Thus, the formation of the common oxocene deriva- of steric hindrance, imposed by the presence of the gem-di- tive 139 was efficiently undertaken by exposure of the acy- methyl system at the allylic position, as the reason for these clic precursor 138 to Grubbs II catalyst (4). For the incorpo- disappointing results, in 2017 Thomas and co-workers ration of the halogen with concomitant intramolecular studied the RCM reaction in model systems of the bryo- etherification, oxocene 139 was previously transformed statins in which the gem-dimethyl group was removed into the alcohol 140 in an excellent overall yield and stereo- 96

(Scheme 11). In their study, the RCM reaction of model selectivity. With this compound in hand, treatment with t- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. compound 132 by exposure to the Grubbs II catalyst (4) fur- BuOCl or NBS efficiently furnished the corresponding nished the macrocyclic compound 133, albeit in a poor 17% chloro and bromo bicyclic ethers, which were prepared for yield (Scheme 11). These results are an indication of the se- the key CM reaction by transformation into the terminal rious hurdles that this class of systems presents for the me- olefins 141 and 142, respectively. For the E-selective instal- tathesis reaction. lation of the enyne moiety, they carried out a CM reaction A recent 2018 example in which a RCM reaction was of compounds 141 and 142 with crotonoaldehyde in the combined with a final CM reaction to append the side chain presence of the Grubbs II catalyst (4) to yield the corre- in a stereoselective manner is the synthesis of the haloge- sponding (E)-α,β-unsaturated aldehydes, which after a final nated marine metabolites chlorofucins 134 and 135 and reaction with lithium TMS-diazomethane delivered the fi- bromofucins 136 and 137 by Paton, Kim, and co-workers nal products 135 and 137 in 74% and 61% overall yields, re- (Scheme 12).97 These natural products belong to the family spectively. For the synthesis of the Z-isomers, they applied of the bioactive acetogenins isolated from the Laurencia red the Lee methodology,99 based on a cross metathesis with algae that have generated great synthetic interest, particu- enyne 145 in the presence of the H-G II catalyst (6) for the larly in the development of efficient methodologies for the direct delivery of the Z-isomers of both natural products

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

134 and 136 in good yields, albeit in modest stereoselectiv- flow, the yield of the macrocyclic product could be in- ities in favor of the Z-isomer (3.8:1 mixture for 134; 4:1 for creased to a 49% yield. Final hydrogenation and methyl 136) (Scheme 12). Finally, the described stereodivergent ether cleavage afforded the targeted natural product in 88% strategy to the chlorofucins and bromofucins allowed con- overall yield (Scheme 13). firmation of the absolute configurations of these natural products by comparison of the spectroscopic properties MeO O a) H-G II (6), toluene HO O and optical rotations of the synthetic compounds with 110 °C those reported for the natural products. (43%)

O a) H-G II (6), toluene O OH H H H 110 °C Br a) Grubbs II Br b) BnO(CH2)3MgBr Br MeO continuous flow Neomarchantin A (146) (4) c) L-Selectride Me Me HO (49%) (94%) (94% over 147 b) H , Pd/C N O H N O H O H 2 Me Me Me Me 2 steps) Me H H BnO H c) BBr3 O 3 O 138 139 140 (88% over 2 steps) d) tBuOCl for 141, or NBS for 142 Scheme 13 Total synthesis of neomarchantin A TIPS O e) H2, Pd(OH)2 145 f) o-NO2-C6H4SeCN; (n-Oct)3P; then H2O2 As a final example for this section, an interesting strate- X H X H H H gy was delineated for the synthesis of the cyclopropane fat- Br i) H-G II (6), C6H6, 70 °C, 145 Br H (Z/E = 3.8:1 for 134, 4:1 for 136); H ty acid (+)-majusculoic acid (148), an interesting secondary O Me O Me j) TBAF H O H H O H metabolite with significant antifungal activity, by Zhang H (88% overall yield for 134) H 103 (73% overall yield for 136) and co-workers (Scheme 14). Accordingly, they devised a 3Z-Chlorofucin (134): X = Cl 141: X = Cl stereoselective cyclopropanation from the C -symmetric 142: X = Br 2 3Z-Bromofucin (136): X = Br 14-membered dilactone according to previously performed g) Grubbs II (4) crotonaldehyde DFT calculations that revealed a preference of the β-faces of both olefins for the attack of the corresponding cyclopro- X H X H H H panating reagents. For the synthesis of the required dilac- Br Br H H tone 150, they envisioned an unusual RCM dimerization O Me h) TMSCH2N2, LDA O Me H O H O from diolefinic monomer 149. To this aim, after an exten- H (74% for 135 H O H over 2 steps) H sive study in which an array of catalysts, solvents, and tem- 3E-Chlorofucin (135): X = Cl (61% for 137 143: X = Cl peratures were screened, they found the Grubbs II catalyst 3E-Bromofucin (137): X = Br over 2 steps) 144: X = Br (4) in refluxing dichloromethane as the best reaction condi- Scheme 12 Total synthesis of chlorofucins and bromofucins tions to obtain the dilactone 150 (53%), accompanied by the monomeric RCM product 151 in 26% yield. With the dilac- Metathesis-based methodologies have been used in tone 150 in hand, it was possible to demonstrate the reli- combination with other innovative technologies in organic ability of the theoretical predictions regarding the stereo- synthesis laboratories. Indeed such a case is continuous chemical outcome of the cyclopropanation. Indeed, the for- flow technology, which has been recently implemented in mation of the biscyclopropane 152 was realized in 80% combination with metathesis reactions to enhance their yield as a single stereoisomer when 150 was treated with synthetic value.100,101 An interesting application of this can diazomethane in the presence of palladium(II) acetate. The be found in the total synthesis of neomarchantin A (146), a dimerization process was then continued by a dedimeriza-

natural product belonging to the macrocyclic bisbibenzyl tion process by opening of the dilactone 152 with N,O-di- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. family, which has been paid much attention from chemical methylhydroxylamine and reduction of the resulting Wein- and biological standpoints due to its intriguing structural reb amide to the aldehyde 153. In a final sequence of eight and biological features. For example, these compounds ex- steps, in which the awkward (E,Z)-bromodiene system was hibit a wide range of biological activities, including antibac- installed via their newly developed new Kocienski–Julia- terial, antimycotic, antitumoral, and antiviral activities. The type reagent 154, the synthesis was complete, obtaining a total synthesis of neomarchantin A (146) (Scheme 13), de- product which matched all the spectroscopic and physical scribed by Collins and co-workers,102 represents the first properties with those reported for the natural product, ex- synthesis of this natural product, which is based on a RCM cept for the optical rotation, which was the opposite. There- reaction of the diolefin 147, to obtain the corresponding fore, this asymmetric synthesis allowed the confirmation of macrocyclic derivative in a modest 43% yield when H-G II the absolute configuration for the natural product that cor- catalyst (6) was employed in toluene at 110 °C. Interesting- responded to ent-148, as initially proposed (Scheme 14). ly, when the cyclization reaction was done in continuous

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

intermolecular assembly of two alkenes, in which di- O TBSO a) Grubbs II (4) TBSO merization processes compete substantially. Despite these O O CH2Cl2, reflux O O O + difficulties, the appealing features of the metathesis reac- (53% for 150) OTBS O O 149 (26% for 151) 151 tions, in terms of functional group tolerance and mild reac- OTBS 150 tion conditions, have prompted intense research activity O N N with the goal of minimizing the chemo- and stereoselective Me O S N b) CH2N2, Pd(OAc)2 (80%) Br N issues associated with this modality. As a consequence, CM Br Ph 154 TBSO reactions have emerged as a common chain-elongation c) NH(OMe)Me O O H method to append small side chains or to assemble linear d) DIBAL-H TBSO H CHO complex molecular frameworks. Concerning the stereose- (82%) H H OH O O lectivity of the reaction, the thermodynamic control that 153 OTBS governs these reactions leads to the preferred formation of 152 (8 steps) the E-alkene. Within the field of total synthesis, several in- Me Br Me Br teresting syntheses of natural products have been reported

CO2H CO2H in which the CM represented the key step for the coupling (+)-Majusculoic acid (148) (–)-Majusculoic acid (ent-148) of the important fragments of the molecule, thus allowing (Absolute configuration for the natural product) the completion of the synthesis. Among the most outstanding contributions of the last few years are the total synthe- Scheme 14 Total synthesis of (+)-majusculoic acid ses of the fluorinated cryptophycin (155),104 FD-891 (156),105 murisolin (157),106 ledoglucomides A (158) and B 2.2 Total Syntheses Based on a Cross-Metathesis (159),107 epicoccamide D (160),108 synargentolide B Reaction (161),109 homaline (162),110 bitungolide F (163),111 penarolide (164),112 cytospolide D (165),113 goniocin (166),114 In contrast to the RCM reactions, the cross-metathesis cryptomoscatone F1 (167),115 curvicollide C (168),116 pro- (CM) reaction has received less attention in the field of total posed structures for cryptorigidifoliol K 169a–d,117 and synthesis, probably due to the inherent difficulties of the alotaketal A (170)118 (Figure 6).

Me CM (43%) Me Me Me Macrolactonization Me O F F O HO O OH O O OH OH OMe C12H25 O O HN F O O Me 5 Me OH OH O F F CM(37%) Me O HN O OH Me Me Me Murisolin (157) Macrolactamization O [106] O CM FD-891 (156) CM(67%) (Haufe, 2012) Me (65%) [105] Me (Yadav, 2012) OAc OH O Me Fluorinated Cryptophycin (155) N O (Sewald, 2012)[104] HO OH OH Me O O N HO O Me OAc OH Ph CM (82%) (84% for 158) HO 7 N OH CM 5 O O O (85% for 159) Me Synargentolide B (161) (47%) O O CM O Me (Akkewar, 2014)[109] Ph O H N HO O N Epicoccamide D (160) Homaline (162) HO [110] N 5 OH [108] (Davies, 2012) Me OH 4 (Yajima, 2014) OH O R Me Me H Me C H H Me Iedoglucomide A: R = Me (158) O 12 25 O H H OH Iedoglucomide B: R = H (159) OSO3Na O O [107] O H O

(Reddy, 2013) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. H N O NaO3SO CM (70%) CM (90%) O Me OSO3Na Me (+)-Goniocin (166) OH (Uenishi, 2016)[114] Macrolactamization O CM (39%) CM (72%) HO Me OH OH O Penarolide (164) Me (47%) O CM (Du, 2014)[112] Me O O Bitungolide F (163) Macrolactonization O H Me [111] Me HO H H (Krishna, 2014) O OH Me Me Cytospolide D (165) Me (Kamal, 2014)[113] Me O O Me Me Alotaketal A (170) O 72% for isomer 169a: S, n = 5, m = 7 Me OH OH OH O CM 74% for isomer 169b: R, n = 5, m = 7 (Tong, 2017)[118] CM (42%) Curvicollide C (168) CM (76%) [116] 70% for isomer 169c: S, n = m = 6 O (Hiersemann, 2017) OH Cryptomoscatone F1 (167) 74% for isomer 169d: R, n = m = 6 (Yadav, 2016)[115] Me O n m Proposed Cryptorigidifoliol K (169) O O (Mohapatra, 2017)[117]

Figure 6 selected natural products synthesized via a CM reaction (yields refer only to the CM reaction)

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

However, there are some specific cases that deserve a O O Me O Grubbs II (4) more detailed description. As a first example within this O + (40%) O category is the formal total synthesis of spirangien A (171), 178 O Me a highly potent cytotoxic spiroketal isolated from the prolif- 179 Mueggelone (177) ic myxobacterium Sorangium cellulosum. Among the various total syntheses described for this natural product, that Scheme 16 Total synthesis of mueggelone reported by Rizzacasa and co-workers (Scheme 15)119 utilized a CM reaction in the union of the olefins 172 and 173 syntheses. Among them, the total syntheses developed by under the assistance of the Grela–Grubbs–Hoveyda catalyst Ghosh and co-workers is based on a CM reaction,122 repre- (10). This CM reaction afforded the E-enone 174 in an ex- senting a brilliant example of the power and robustness of cellent 80% yield, providing a straightforward alternative to the methodology (Scheme 17). the use of a Horner–Wadsworth–Emmons reaction, which Me requires additional steps for the preparation of the required H Me N phosphonate. In this way, the backbone of the spiroketal O + O core found in the natural product was constructed, requir- O O O Me Me O Me a) Grubbs II (4) Me (71%) ing only six additional steps for the rapid and efficient 183 184 Me preparation of the spiroketal precursor 176. From the ad- H Me N vanced spiroketal precursor 176, the completion of the nat- O ural product was reported earlier by Paterson and co-work- O O O O Me Me O Me ers (Scheme 15).120 Me Spliceostatin E (180) O Me Me Me Me H OH Me N PMBO O O MeO O O O OBn O a) Grela-Grubbs- Me + O + Hoveyda (10) O O Me Me O Me a) Grubbs II (4) OMe (80%) Me (57%) Me Me Me Me Me Me 185 186 172 173 O H Me Me Me Me OH Me N b) Mn(dpm)3, Ph3SiH O O2, then P(OEt)3 (61%) PMBO O O MeO O O O OBn Me O c) CSA, MeOH (78%) O O Me Me O Me d) TESOTf; e) DDQ (79%) OR Me Me Me Me Me Me Me e) I2, Ph3P, imidazole (95%) b) PPTS Spliceostatin A (181): R = Me 174 f) FeCl3, TMEDA, 175 (84%) (79%) FR901464 (182): R = H g) LiDBB (97%) MgBr Me Scheme 17 Total synthesis of spliceostatins E and A and FR901464 Me OTES Me Me 175 Me MeO OH CO H MeO O 2 [Paterson, 2009]120 O OTES The ability of these natural products to inhibit the cellu- Me Me Me OH lar splicing process, an essential step for the gene expres- Me Me Me Me Me sion, renders them a novel class of anticancer products. In O OTES MeO fact, spliceostatin E (180) and FR901464 (182) exhibit po- 176 O OH Me Me Me Spirangien A (171) tent anticancer activities in the ranges from 1.5 to 4.1 and Me Me from 0.6 to 3.4 nM, respectively, against various human OH cancer cell lines. The syntheses of both compounds were

Scheme 15 Formal total synthesis of spirangien A achieved via a final key CM that efficiently joined fragments This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 183 and 184 for spliceostatin E (180)122 and 185 and 186 for Another case of note is represented by the total synthe- spliceostatin A (181),123 in 71% and 57% yields, respectively, sis of mueggelone (177), an inhibitor of fish embryo larval with both reactions displaying exquisite chemo- and stereo- development. After several total syntheses reported for this selectivities. A final acidic treatment of compound 181 af- interesting natural product, some of which required around forded the natural product 182 (Scheme 17). 20 steps, Meshram and Kumar121 described a convergent An excellent example that illustrates the advantage that total synthesis utilizing only eight steps in the longest lin- the CM reaction can offer, especially for macrocyclic com- ear sequence, featuring a final CM step in which olefins 178 pounds, over a RCM reaction, are the synthesis of the natu- and 179 were assembled by treatment with the Grubbs II ral products mycalolide A (187) and B (188) by Kigoshi, catalyst (4) to directly deliver the natural product 177 in Kita, and co-workers (Scheme 18).124 Both compounds, iso- 40% yield (Scheme 16). lated from the marine sponge Mycale sp., are members of a The prominent antitumor activities of spliceostatin E family of natural products characterized by the presence of (180) and related compounds, such as spliceostatin A (181) a trisoxazole macrocycle with potent cytotoxic activities as and FR901464 (182), have elicited great interest in their a consequence of actin-depolymerizing activity. A first at-

Syn thesis I. Cheng-Sánchez, F. Sarabia Review tempt at the total synthesis was carried out by them via a tempted a CM/macrolactonization approach which proved RCM reaction of the diolefins 189a and 189b. However, de- to be more efficient. Thus, when a mixture of olefins 191 spite this reaction affording the macrocyclic derivatives and 192 was subjected to the catalytic action of the H-G II 190a and 190b in reasonably good yields (40–76% depend- catalyst (6) in refluxing dichloromethane, the olefin 193 ing on the employed catalysts and solvents), the reaction was obtained in an impressive 77% yield and in an improved was not stereoselective in either case, providing a mixture 5:1 mixture of the E/Z isomers. After the successful CM of the E/Z isomers in ratios of 1:1 to 1.9:1.0. This proportion step, a Yamaguchi macrolactonization was conducted to could be increased to a 2.7:1.0 ratio in favor of the required prepare the corresponding macrolactone in a remarkable E-olefin when the desilylated derivative 189b was em- 77% yield, which was finally directed to the natural prod- ployed as the starting precursor. As an alternative, they at- ucts mycalolides A (187) and B (188) in ten additional steps (Scheme 18). MeO O The scope of the CM reaction has been expanded to con- DMPMOM = O 125 O jugated dienes by Altmann and Glaus in 2015 during N Me OMe their synthetic studies directed towards the aglycone of OMe N RO tiacumicin B (194), a macrocylic antibiotic with potential O DMPMOM OMe application against Mycobacterium tuberculosis and whose O O H–G II (6), or N MeO OMe O O Grela (10), or total synthesis was not reported when the studies were O Zhan (11) published (Scheme 19). Thus, combination of olefin 195 Me Me Me Me (40–76% for 190a) and the conjugated diene 196 in the presence of the H-G II 189a: R = TBDPS (63% for 190b) 189b: R = H MeO O catalyst (6) provided a 56% yield of compound 197 as an inseparable mixture of E/Z isomers in a 6.7:1 ratio. The prepa- O N Me ration of ester 199 was followed by a Suzuki macrocycliza-

N RO O DMPMOM OMe OTBS O O E/Z = 6.7:1 N MeO OMe O O TBSO O TBSO O Me MeO Me Me Me Me 196 Me OTBS (E/Z from 1.0:1.0 to Me 190a: R = TBDPS Me a) H–G II (6) Me O 2.7:1.0) 190b: R = H TESO I EtOAc, r.t. Me MeO MeO O (56%) TESO I 195 197 O OH d) Yamaguchi O TES DMPMOM OMe b) LiOH N Me esterification MeO O OMe O O B Me c) TESCl; K CO O 2 3 with 198 (68% overall) TBDPSO Me OTBS N + R2O 198 TBSO O Me Me Me Me O OTCE N Me OR2 Me OTBS a) H–G II (6) 192 191 e) [Pd(PPh3)4], TlOEt O CH2Cl2, reflux Me O Me O (77%) Me MeO Me (73%) Me O Me MeO O R1O TESO I OR2 OTBS

O 1 2 N Me f) Et3N 3 HF 200: R = TES; R = TBS Me O (47%) 1 2 Tiacumicin B aglycone (194): R = R = H 199 Bpin N TBDPSO OTCE OMOM O BnO Not reported

DMPMOM OMe This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. TES BnO O N MeO O OMe O O Me OMOM SEMO O Me 202 Me COOSEM Me Me Me Me Me TBS Me Me E/Z = 5:1 193 a) H–G II (6) Me MeO Me toluene, 100 °C TESO TESO OBn MeO O (38%) (11 steps) OBn O OAc Me 201 203 TBSO Me O N O N Me 30 Ph MPMO E/Z = 86:14 OMe Me Me H MPMO OTBS N HO OMe Mycalolide A (187) Me OTBS O O O Me O 205 N MeO OMe O O OAc Me HO Me CO2H Me Me N O Me H a) Grubbs II (4) O 30 Me MeO Me R O CH Cl , 40 °C 1 Me Me Me Me H MOMO 2 2 OMPM OMPM (39%) 204 206 Mycalolide B (188) HO Me Scheme 18 Total synthesis of mycalolides A and B Scheme 19 Total synthesis of tiacumicin B aglycone

Syn thesis I. Cheng-Sánchez, F. Sarabia Review tion, to afford the macrocyclic aglycone derivative of an exhaustive comparative analysis of the NMR data of a tiacumicin B (200) in 73% yield. Global desilylation of the wide set of acetogenins possessing a 4-hydroxy group adja- macrocyclic derivative 200 was performed with Et3N·3HF to cent to the γ-lactone ring, together with a detailed analysis obtain tiacumicin B aglycone (194). In 2015, Gademann and of the MS fragmentations, they were led to propose the co-workers reported the total synthesis of tiacumicin B, structure of the natural product montanacin D (212), also named fidaxomicin or lipiarmycin A3 (53), based on a whose synthesis was similarly accomplished by them ac- RCM strategy, as depicted in Figure 3.59 In addition to the cording to the same CM strategy, for the revised structure synthetic studies by Altmann and Glaus,125 closely related for aromin (Scheme 20).128 strategies have been reported by Zhu and co-workers 126 127 Me O (2015) and Roulland and co-workers (2017), also using O O CM reactions (Scheme 19). The former achieved the assem- Me OTBS OTBS O O + SPh bly of olefin 201 and diene 202, while the latter carried out 209 a) Grubbs II (4) CH2Cl2, 40 °C the assembly of olefin 204 with diene 205 to yield the cor- 208 responding CM products 203 and 206 in 38% and 39% Me (68%) O b) H , PtO yields, respectively and with stereoselectivities comparable 2 2 OTBS OTBS O O c) mCPBA O to those obtained by Altmann and Glaus. However, unlike d) toluene (73% O Me 3 SPh 110 °C overall yield) the studies of Altmann and Glaus, in these cases they found 210 serious difficulties, mainly with the subsequent removal of e) HF·pyr Me the employed protecting groups within the products 203 O and 206, thus forcing them to explore different synthetic OH OH O O O Me Aromin (207) strategies in both cases, to overcome these synthetic hur- 3 O (Originally proposed structure) dles and to reach the targeted tiacumicin B aglycone (194). Me Another relevant contribution of the use of the CM reac- O tion in total synthesis was published in 2016 by Takahashi OH OH O O Me Stereoisomer 211 and co-workers for the total synthesis of aromin (207) O 3 O (Scheme 20),128a a member belonging to the wide family of Me the Annonaceous acetogenins , isolated from the Annonace- O ae plants and which exhibits a broad spectrum of biological OH OH O O O Me Montanacin D (212) activities including anticancer, antibiotic, immunosuppres- O 2 (Proposed revision for Aromin) sive, antifeedant, and pesticidal activities. Aromin (207), CM (78%) isolated together with aromicin in 1996 by McLaughlin and Scheme 20 Total synthesis of proposed structure for aromin and its 129 co-workers, has been recognized as an antitumoral com- structural revision pound with a significant cytotoxicity profile against various tumor cell lines, albeit lower compared to other acetogenins. The synthetic work by Takahashi and co-workers,128a Another interesting application of the CM reaction was based on their previous synthetic work,128b is interesting for the recent total synthesis of depudecin (213) by Sarabia and two reasons. On one hand, they demonstrated the utility of co-workers,130 in which functional group tolerance provid- the CM reaction by using the Grubbs II catalyst (4) to con- ed by the employed catalysts was verified, in particular nect a terminal olefin and an enone to construct the corre- with the especially sensitive oxirane rings (Scheme 21). sponding linear E-enone. On the other hand, this work also Depudecin represents an unprecedented natural product

led to the structural revision of aromin (207). Thus, the as- that selectively inhibits histone deacetylases I and II in the This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. sembly of olefin 208 and enone 209 proceeded smoothly low μM range. With respect to its total synthesis, the con- when they were exposed to the Grubbs II catalyst (4) to struction of the complete framework of depudecin was ac- provide the E-enone 210 in 68% yield and excellent stereo- complished via an efficient CM reaction of epoxy olefin 214 selectivity. With this compound 210 in hand, they accom- and diepoxy olefin 215 by using the H-G II catalyst (6) to plished the completion of the proposed structure for arom- obtain the resulting triepoxy olefin 216 in a reasonable 50% in in four additional steps in 73% overall yield. Surprisingly, yield, exclusively as the E-isomer. With the product 216 in the spectroscopic and physical properties of the synthetic hand, its transformation into the final natural product was material 207 were notably different from those reported for successfully achieved, requiring the reductive opening of the natural aromin. According to the detected discrepancies the terminal epoxy alcohol, carried out in three steps, and found in the 1H NMR spectra, they suggested a structural final removal of the protecting group of the resulting prod- difference around the central THF ring and, for this reason, uct 217 (Scheme 21). It is important to point out that this they prepared the stereoisomer 211, according to a similar total synthesis represents the third total synthesis reported synthetic sequence as for 207, but once again, the NMR data thus far for this interesting molecule, resulting in an im- were inconsistent with those of the natural product. After provement upon the previous syntheses reported by Sch-

Syn thesis I. Cheng-Sánchez, F. Sarabia Review reiber and co-workers in 1990,131 and also by Sarabia and lide A (222) and aspinolide A (223) matched with those re- co-workers group utilizing a linear strategy.132 In addition, ported for the natural products putaminoxins B/D (Scheme the new convergent CM synthetic strategy provided rapid 22). access to different stereoisomers of depudecin, which allowed for an evaluation of the influence of the stereochem- OTHP O OEt istry upon biological activities. OAc (S)-220 OAc OTHP O C H (R)-220 5 11 9 5 C5H11 C5H11 OEt OTBDPS a) Grubbs II (4) OAc (S,S)-219 (36% for 221a) 221a: (5R,9S) Me (R,R)-219 221b: (5S,9S) O (72% for 221b) OTBDPS 221c: (5R,9R) 214 (24% for 221c) a) H–G II (6) OH 221d: (5S,9S) Me (83% for 221d) O O O b) LiOH CH2Cl2, 40 °C 216 c) Yamaguchi OH (50%) O d) PPTS O O b) TsCl O c) KI (90% over 3 steps) O 215 5 218a: (5R,9S) d) BuLi C H 9 OH 5 11 218b: (5S,9S) O Proposed structures for 218c: (5R,9R) 5 OH OTBDPS Putaminoxins B/D 218d: (5S,9S) C H 9 OH e) TBAF 5 11 Me Me O O O O O O OH (90%) OH (–)-Depudecin (213) 217 O O

Scheme 21 Total synthesis of depudecin C7H15 OH Me OH Hypocreolide A (222) Aspinolide A (223)

Scheme 22 Total synthesis and structural studies of putaminoxins B/D A final example within this section is represented by the interesting synthetic strategy reported by Pietruszka and co-workers for the synthesis of putaminoxins B/D 2.3 Strategies for Selective and Efficient Metathe- (218), identified as a C-9 epimeric mixture and whose ab- sis Reactions of Alkenes solute configurations were not yet established (Scheme 22).133 In order to unambiguously establish their absolute 2.3.1 Temporary Tethered Ring-Closing Metathesis configurations, the four possible stereoisomers 218a–d were prepared by a CM reaction of dimers (S,S)- and (R,R)- A highly inventive and clever strategy to transform the 219, previously prepared by a dimerization CM reaction of intermolecular character of the cross-metathesis of alkenes the corresponding monomers, with olefins (S)- and (R)-220. into an intramolecular variant has been explored by means The choice to use the dimers 219 instead of the correspond- of the development of temporary tethers, through which ing monomeric olefins was justified because better yields the corresponding olefinic partners can be transiently cou- were obtained for the desired cross-metathesis products pled. This strategy not only provides the advantage of im- 221 versus CM reactions with the monomers, in which the proved efficiency, which is a feature of RCM versus the CM dimeric products 219 were the main compounds detected. reaction, but also the possibility of controlling the geome- Indeed, when each isomer of 219 was treated with the cor- try of the resulting double bond to favor the Z-olefin when responding (S)- and (R)-220 in the presence of the Grubbs II a strained ring is temporarily formed. However, this strate- catalyst (4) the corresponding products 221a–d were ob- gy is limited to molecular structures in which a possible tained in 36%, 72%, 24%, and 83% yields, respectively. Then, linkage of the tether system is present, usually in form of each isomer was subjected to a sequence that included ba- hydroxy groups at allylic or homoallylic positions. Due to

sic treatment, a Yamaguchi macrolactonization and final the versatility, stability, and ease of cleavage, silicon-based This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. THP protecting group removal to provide all the possible tethers have been the most frequently employed for this stereoisomers of the macrolactone 218 in high yields. With strategy. In fact, the temporary silicon-tethered RCM (TST- all the isomers in hand, an extensive spectroscopic study, in RCM) was described initially by Grubbs and Fu in 1992.134 which they compared the NMR data collected from all these Thus, in order to favor the formation of the Z-isomer, a tem- compounds with those reported for the natural products, porary [7]-membered ring is required, for which the silicon resulted in disappointment. This was due to the inability to tethered is represented by precursor A. In case of precursor correlate the resulting NMR data of the synthetic com- B, whose RCM would deliver an [8]-membered ring, the pounds with those reported for the natural products, thus preference would be the formation of the E-isomer (Scheme leading them to reconsider the initially proposed structures 23, A). In 2012, the applications of silicon-tethered RCM in for putaminoxins B/D. Intriguingly, after a thorough inspec- synthesis of natural products was reviewed135 and, as a con- tion of the NMR data of related nonenolides, they found sequence, in this section, we will focus on recent examples that the data reported for the natural products hypocreo- published after 2012, together with other cases of tethered RCM reactions based on other tethers and their applications in the total synthesis of natural products. Some relevant

Syn thesis I. Cheng-Sánchez, F. Sarabia Review contributions to this field are those by Kobayashi,136 ment with methyllithium, to deliver compound type B. The Hoye,137 and Evans,138 as well as numerous syntheses of nat- resulting alcohol 232 was then coupled with silane 233 via ural products belonging to the family of 6-substituted 5,6- a dehydrogenative reaction, mediated by a catalytic amount dihydro-α-pyrones, such as hyptolide (224),139 pectinolide of (Xantphos)CuCl and in the presence of lithium tert-bu- C (225),140 and umuravumbolide (226),141 all of which have toxide, to afford the targeted precursor 234 in an excellent been efficiently achieved according to this strategy from yield and exquisite control of the geometry of the double precursors 227, 228, and 229, respectively (Scheme 23, B). bonds. Promptly, with compound 236 in hand, they proceeded with the connection of the other important frag- A) ment of the molecule via a cross-aldol condensation to pro- R R' R R' vide aldehyde 237 in a sequence of seven steps, followed by O O O O Si Si Ph Ph Ph Ph a Yamaguchi macrolactonization that provided macrocyclic A [7]-membered ring derivative 238. The completion of the synthesis from this advanced precursor was then executed in five steps, con- R R' R R' sisting of a Sharpless asymmetric epoxidation from the cor- O O O O Si Si responding allylic alcohol, reductive opening of the result- Ph Ph Ph Ph ing diepoxy alcohol, and final removal of the trimethylsilyl B [8]-membered ring group. Me Me B) TST-RCM O (75%) Me Me Si OAc OAc O OBn O O R' Me Me OPMB [Ru] R' n MeLi R' OTBS n Me n OAc Si Me Si Hyptolide (224) 227 Me Si O R 3 HO R O R Me [Kumar, 2013]139 Me A B Me Me TST-RCM O (85%) Me Me Me Si Me c) (Xantphos)CuCl O O Ph O a) Grubbs I (3) t OAc O Si BuOLi (97%) Me Me b) MeLi Me OH SiMe Ph (70% over HO 3 Ph OBn Si OH 2 steps) H Me Ph Pectinolide C (225) 228 231 232 [Rao, 2013]140 Me Me OPMP 233 TST-RCM O Me (89%) Me Me Si O O Ph SiMe OAc O Ph 3 Ph Ph Me Si O Me d) Grubbs II (4) Si SiMe3 O CO2Me Me (96%) Umuravumbolide (226) 229 e) Re O Ph [Rao, 2013]141 2 7 (85%) OPMB 235 OPMP 234

Scheme 23 General temporary silicon-tethered RCM (TST-RCM) reac- Ph Ph tions and selected natural products synthesized via this strategy Si Ph Ph O Si O O E/Z = 85:15 (7 steps) Me In addition to silicon-tethered RCM reactions containing Me O an O–Si–O linkage, this strategy has also been utilized with OPMP SiMe3 substrates containing an O–Si–C linkage, in which an oxida- 236 SiMe3 CO2Me tive or base-induced ring cleavage step is required after the O 237 HO c) Cl C H COCl RCM reaction. Prominent amongst these cases is the 2013 Me a) AgF 3 6 2 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. DIPEA, DMAP b) Me SnOH synthesis of the potent cytotoxic natural product amphid- O 3 (39% over 142 3 steps inolide V (230) by Lee and Volchkov (Scheme 24), in O d) NaBH O which the stereocontrolled construction of the existing 4 O Amphidinolide V (230) e) Sharpless SiMe3 double bonds was devised utilizing a tethered RCM of silyl f) I2, PPh3 ether 234 that provided the RCM product 235 in an excel- g) tBuLi O Me lent 96% yield, which was then subjected to an allylic 1,3- h) AgF (38% over 5 steps) O 238 transposition mediated by Re2O7 to afford siloxane 236 as an 85:15 E/Z inseparable mixture in 85% yield. The presence Scheme 24 Total synthesis of amphidinolide V of the trimethylsilyl group in the 1,3-diene subunit was proven to be critical to prevent unwanted side reactions during the metathesis reaction. The RCM precursor 234 was The use of this strategy for the selective construction of prepared beforehand via an enyne RCM of silyl ether 231 to a trisubstituted Z-olefin is nicely illustrated in the synthesis furnish a cyclic siloxene type A, according to the general re- of the important antimitotic agent epothilone B (239), in action depicted in Scheme 24, which was opened by treat- which the required Z-olefin at the C12–C13 bond has been

Syn thesis I. Cheng-Sánchez, F. Sarabia Review a critical issue, and which different solutions across the vast lides isolated from marine dinoflagellates with potent cyto- number of reported synthesis of this natural product have toxic activities. Structurally, the so-named amphidinolides been found.143 Thus, whereas a conventional RCM of an ad- of the T series are characterized by the presence of a trisub- vanced diolefin precursor was devoid of stereoselectivity, a stituted tetrahydrofuran. In the case of amphidinolide T1 silicon-tethered RCM reaction initially explored by Mulzer (245), the synthesis of the C1–C11 fragment was initially and Gaich provided the required Z-isomer with a remark- attempted by utilization of a CM reaction to connect the able 5:1 selectivity albeit through a long synthetic se- corresponding olefins, but all attempts were thwarted to quence.144 In a shorter and rapid approach, Lin and co- obtain the desired CM product. The implementation of a workers explored the RCM reaction through the formation tethered RCM strategy to prepare this fragment was then of a bissiloxane-tethered precursor, to secure the double attempted via a temporary ester, for which diolefin ester bond geometry (Scheme 25).145 To this aim, the precursor 246 was prepared, but again, the reaction was found to be 242, efficiently prepared by joining segments 240 and 241, unsuccessful, instead obtaining the RCM product 247. In was subjected to the Grubbs II catalyst (4) to yield the cor- light of these discouraging results, the use of a salicylate responding RCM product 243 in nearly quantitative yield spacer as an alternative ester-tether RCM was explored; in- (95%) as a 1.7:1 mixture of Z/E isomers, which could be sep- deed the treatment of 248 with the Hoveyda–Grubbs I cata- arated after selective cleavage of the silicon-tethered by re- lyst (5) afforded an isomeric mixture (E/Z 1.2:1) of the lac- action with HF·pyridine. Notably, despite the moderate se- tone 249 in an impressive 96% yield. The removal of the lectivity of the RCM reaction, the required aldehyde 244 in spacer group was carried out by base treatment, followed the form of the pure Z-isomer was obtained in 40% over by a chemoselective hydrogenation to complete the west- three steps, representing the most step-economic synthesis ern fragment of the natural product in form of the product reported thus far. From aldehyde 244, the completion of the 250. The coupling of this fragment with the eastern frag- synthesis of epothilone B was accomplished in an efficient ment provided access to the corresponding seco acid, which manner in six steps, with a TiCl4-mediated aldol reaction was subjected to a Yamaguchi macrolactonization to pro- and a Yamaguchi macrolactonization as the key steps (Scheme 25). O O 11 O 1 Me S Me H Me various catalysts H Me O Me S O O N Me i i Me H H a) ClSi( Pr)2OSi( Pr)2Cl, DBU OH 240 N 246 (82%) O O O 247 Me Me i Si Si Pr i iPr iPr Pr O Me 241 242 O OH (95%) O O b) Grubbs-II (4) a) H–G I b) KOH, MeOH O O H (5) H c) H2, [Ir] (Z/E = 1.7:1) O O Me Me O O Me (96%) H Me H (85% over Me S Me S E/Z = 1.2:1 Me Me 2 steps) Me N c) HF•pyr N 248 249 OH O F O O d) DMP O O i Me Si Si i Me i Pr H i i Pr (42% overall Pr Si Si Pr Pr i O i Pr for isolated Z-isomer) iPr Pr (4 steps) O 244 243 H Me H CO2Me (6 steps) O [Macrolactonization] H Me O 250

Me Me This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O S O OH Me 251 Me O Me HO Me N Me O (44% for 252 a) (EtO)2MeSiH Me Me H 45% for 253) [Cp*Ru(MeCN)3]PF6 O O OH O Me H Epothilone B (239) O Me Me Me Me O Scheme 25 Total synthesis of epothilone B EtO Si EtO Si Amphidinolide T1 (245) EtO EtO The extension of the concept of a temporary tethered Me Me H H + RCM to other groups such as esters or acetals would expand O Me O O Me O b) mCPBA H H the synthetic opportunities that this strategy might offer. c) KHF2, H2O2 O O (73% over 2 steps) One such application is elegantly illustrated with the total 253 252 syntheses of amphidinolides T1, T3, and T4 by Clark and Ro- Amphidinolide T3 and T4 miti (Scheme 26).146 As for amphidinolide V, discussed above, the amphidinolides T1, T3, and T4 are also macro- Scheme 26 Total synthesis of amphidinolides T

Syn thesis I. Cheng-Sánchez, F. Sarabia Review vide 251, representing the macrocyclic core of the amphid- virtue of its inhibition of mitochondrial complex I. In this inolides T. The completion of the synthesis of this natural synthetic proposal, precursor 260, readily prepared from a product was achieved with the hydrosilylation of the C2 symmetric diene diol, was treated with the Grubbs II alkyne present in 251 using the ruthenium catalyst catalyst (4) to obtain the resulting RCM product, as a result

[Cp*Ru(MeCN)3]PF6 that afforded a 1:1 mixture of isomeric of a multiple RCM process. In a second step, the assembly of (Z)-vinylsilanes 252 and 253 that could be separated by the resulting polyene and 10-chlorodec-1-ene was induced chromatography. Whereas, 252 was transformed into am- by treatment again with the Grubbs II catalyst (4) to deliver phidinolide T1 (245) via epoxidation of the vinylsilane, fol- the complete framework of this class of natural products in lowed by a Fleming–Tamao oxidation, the product 253 pro- form of compound 261. Finally, the completion of the syn- vided amphidinolides T3 and T4 under the same synthetic thesis of this stereoisomer of squamocin K was achieved in sequence (Scheme 26). 12 additional steps, including the formation of the required The ester-tethered RCM was similarly used in the syn- tetrahydrofuran rings, via previous activation of the result- thesis of polyacetylene-type metabolites, such as the atrac- ing hydroxy groups as mesyl derivatives and subsequent in- tylodemaynes C (254) and F (255) by Schmidt and Audörsch tramolecular displacements to afford 262, and the final in- (Scheme 27),147 as a way of controlling the geometry of the troduction of the unsaturated lactone (Scheme 28). depicted double bonds. According to a tandem RCM/base- induced eliminative ring opening, carried out in one pot, a) Grubbs II (4) BnO O O O O OBn (67%) BnO O O O O OBn they were able to construct a E,Z-diene derivative, found in b) Grubbs II (4) these natural products. Thus, when compound 256 was (CH ) Cl 2 8 261 260 treated with the Grubbs II catalyst (4), followed by NaHMDS (70%) Cl(H2C)8 (CH2)8Cl and Meerwein’s salt, compound 257 was obtained in 73% OH OH overall yield through intermediates A, B, and C. Starting C H O O Me 10 21 21 14 9 (6 steps) from the resulting ester 257, the installation of the O O Squamocin K (258) enediyne moiety of the atractylodemaynes C and F was OBn OBn (6 steps) achieved without issues via alkynyl homologation and a So- O O Cl(H2C)10 (CH2)10Cl nogashira coupling (Scheme 27). OH OH O O 262 C10H21 21 14 9 Me O O O a) Grubbs II (4) O O 14,21-di-epi-squamocin K (259) O CH2Cl2, 40 °C O O Scheme 28 Total synthesis of 14,21-di-epi-squamocin K O then NaHMDS O O O O O Ph Ph Ph 256 A B A unique tether for a RCM reaction was employed by Hanson and co-workers in the synthesis of strictifolione 149 O O (263) (Scheme 29, A), a natural product isolated from the EtO then Et3OBF4 O O stem bark of Cryptocaria stritifolia with antifungal activi- (73%) O O O ties. In their synthesis, they used a phosphate-tether that Ph 257 Ph allowed in one pot, a sequential RCM, CM, and a chemose- C lective hydrogenation process, followed by a one-pot, sequential reductive allylic transposition/tether removal and

final CM. To this end, olefinic phosphate 264 was treated This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. AcO O AcO O O O Me with the H-G II catalyst (6) and then, after solvent evapora- Me tion, addition of cis-stilbene in DCE and heating at 60 °C for Me OH Me OAc S-Atractylodemayne F (255) S-Atractylodemayne C (254) two hours. The subsequent chemoselective diimide reduction provided phosphate 265 in 52% overall yield. The fol- Scheme 27 Total synthesis of S-atractylodemayne C and F lowing one-pot protocol was initiated with the reaction of

265 with Pd(OAc)2 in the presence of formic acid, cesium

As an alternative to the silicon-tethered RCM reaction, carbonate, and PPh3 to produce a reductive allylic transpo- the use of acetals to connect both olefinic partners has also sition, followed by addition of methyl sulfate and treatment been developed and applied in 2013 in the synthesis of a with LiAlH4 to furnish diol 266 in 65% overall yield. A final stereoisomer of squamocin K (258), the 14,21-di-epi isomer CM reaction with vinyl lactone 267 in the presence of the 259 by Hou and co-workers (Scheme 28).148 Squamocin K, H-G II catalyst (6) provided the natural product strictifoli- as other Annonaceous acetogenins, displays a wide range of one (263) in 77% yield (Scheme 29, A). In a similar strategy, biological activities, such as antitumor, antiparasitic, pesti- they described the synthesis of the antifungal macrolide cidal, antimicrobial, and immunosuppressive activities, by Sch-725674 (49) (Scheme 29, B),150 wherein the phosphate

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

268 was treated in a similar one-pot RCM/CM/chemoselec- the same year,152 many syntheses have benefited enor- tive hydrogenation sequence as described for 264, with the mously from this strategy as a method to surmount the in- use of alkene 269 to obtain compound 270 in 59% yield. The stances in which RCM reactions proved ineffective or slug- removal of the phosphate tether was accomplished by gish, mainly due to steric factors, as well as electronic fac- 153 treatment with LiAlH4 and, then, after a sequence of trans- tors. A representative example to illustrate the formations, including selective protection of the 1,3-diol implementation of this strategy and its dramatic effect can system as an acetal, Sharpless asymmetric epoxidation of be found in the 2012 synthesis of the cytotoxic natural the resulting allylic alcohol, selective tosylation of the pri- product penostatin B (273) by the Shishido and co-workers mary alcohol, and introduction of the acryloyl unit, provid- (Scheme 30).154 Having devised a RCM strategy for the ed compound 271. This compound was set up for a reduc- preparation of the dihydropyran system contained in the tive opening process, which was carried out in one pot by natural product, the examination of this reaction with the sequential treatment with NaI, Zn, and acidic work-up, to acyclic precursor 274 by using various catalysts and differ- deliver diolefin 272. In contrast to a direct RCM reaction of ent reaction conditions provided the desired unsaturated δ- diolefinic triol 272, carried out by Prasad and co-workers lactone 275 in a modest 46% yield, as the best case, when (see Figure 3),55a that afforded the natural product in a the H-G I catalyst 5 was employed. In an effort to improve modest 36%, Hanson and co-workers found that prior pro- upon this yield, they made use of the relay RCM strategy, for tection of compound 272 as the MOM derivative resulted in which precursors 276 and 277 were prepared. The treat- a more efficient RCM process to provide the final product ment of these compounds with the H-G I catalyst 5 provid- 49 in 84% yield after removal of the protecting groups with ed the RCM product 278 in improved 78% and 83% yields TFA (Scheme 29, B). from 276 and 277, respectively, demonstrating the synthetic value of this strategy. With compound 278 in hand, the A) O O introduction of the alkenyl appendage was successfully P a) H–G II (6); P O O OO then OO achieved from acetyl pyranoside 279, via vinylstannane 280

Ph Ph in a highly stereoselective manner. Finally, the manipula- Ph 264 265 tion towards the final product was undertaken in six addi- then o-NBSH, Et3N (52% overall) b) Pd(OAc)2, HCO2H tional steps. Ph3P, Cs2CO3 (65%) c) Me SO 2 4 BnO BnO O d) LiAlH H H 4 O O Different catalysts and O O OH OH conditions OH OH O H-G II (6) H H H H Ph (0–47%) Me Ph (77%) O H H Strictifolione (263) 266 O O 274O 275

BnO BnO 267 H H O O a) H-G I (5) O O b) DIBAL-H B) O O R H H CH2Cl2, reflux H H c) Ac2O, Et3N P P O a) H-G II (6), CH Cl , reflux; then O (78% from 276 Me OO 2 2 OH OO H H H-G II (6), DCE, reflux 83% from 277) O OH C H O 276: R = H O 278 5 11 5 268 270 277: R = Me C H b) LiAlH4 5 11 C7H15 269 O c) BF3·OEt2, Bu Sn BnO c) 2,2-DMP, CSA (44% over H H 3 280 H then o-NBSH, Et N 3 d) Sharpless 5 steps) O C7H15 d) K2CO3, MeOH O OAc (59% overall) e) TBSOTf e) TsCl, Et3N H H H f) Acryloyl chloride Me Me H f) LiDBB, MgBr2·OEt2 H

O g) TPAP, NMO This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. OH OH TsO AcO HO Penostatin B (273) h) LDA, TMSCl; then Pd(OAc) 279 HO j) MOMCl (97%) g) NaI 2 k) Grubbs II (4) h) Zn, EtOH (27% over 9 steps) i) HF•pyr HO O l) TFA i) aq. HCl HO Me HO Scheme 30 Total synthesis of penostatin B (84%) (79%) Me O O O one-pot O O one-pot steps k-l O O C5H11 In the development of an enabled and flexible strategy C5H11 C5H11 Sch-725674 (49) 272 271 for the synthesis of the cyclodepsipeptidic-like natural Scheme 29 Total synthesis of strictifolione and Sch-725674 products related to the jasplakinolide/geodiamolide family, Arndt, Waldmann, and co-workers designed a divergent solid phase synthesis for this class of compounds based on a 2.3.2 Relay Ring-Closing Metathesis unique RRCM strategy on solid phase to construct the macrocyclic core, directing the catalyst’s action to the required Since the pioneering work of the Hoye group on the re- break point (Scheme 31).155 With the preparation of a PS lay ring-closing metathesis (RRCM) concept in 2004,151 and resin for the linkage of the peptidic chain, which carried a the first application in total synthesis by the Porco group in diene unit, the acyclic precursor loaded onto the resin (res-

Syn thesis I. Cheng-Sánchez, F. Sarabia Review in 281) was synthesized in an efficient manner. The subse- B.157 Despite the formation of the E-isomers being generi- quent reaction with the Grubbs II catalyst (4) delivered the cally favored in these reactions for thermodynamic reasons, protected cyclodepsipeptide 282 in 34% yield as a 1:1.2 there are numerous cases in which the small energy differ- mixture of a separable E/Z isomers, through the formation ence between the E and the Z isomers results in a mixture of the carbene intermediate A with the concomitant release of both geometric isomers. In view of this situation, the de- of resin 283. The removal of the protecting groups of each velopment of catalysts that promote kinetically E-selective pure isomer afforded natural product seragamide A (284) processes represents a new challenge. In response to this and its Z-isomer. In a similar fashion, a collection of jas- requirement, Grubbs and co-workers have described the pamide analogues were generated for biological studies as first catalysts capable of generating E-olefins starting from antitumor agents.155 E-olefins as the reactants.158 These catalysts are a new generation of catalysts that are termed stereoretentive olefin OTIPS metathesis catalysts, and they feature the presence of a cy- I TIPS 22,159 O clic catecholthiolate unit (catalysts 24–27 in Figure 1) Me Me and proceed through intermediates of type C. To this arse- Me N I Me HN H nal of valuable and useful catalysts developed in the last RRCM Me N O N OtBu O O NH few years one must also add chiral catalysts, with which it a) Grubbs II Me O O Me O Me (4) O O O is possible to perform asymmetric olefin metathesis,61,160 as HN O O OtBu (34%) Me described in Scheme 8. A detailed description of the design Me Me Me Me and development of these new selective catalysts, as well as 281 Ru O Me their applications in the synthesis of natural products, has A been widely covered in various reviews.161 Nevertheless, we 283 would like to summarize in this section relevant examples HO TIPS O of selective RCM and CM reactions as representative appli- I Me H cations that prove the synthetic validity and potential of I Me Me N H N OH Me N this new generation of catalysts. Thus, Scheme 32 summa- b) TFA N OtBu Me O c) TBAF rizes examples of Z-selective RCM reactions156,162 and O O O Me O O O O HN O 65% for E-284 Scheme 33 shows cases of Z-selective CM reactions163 in the Me Me HN O 59% for Z-284 Me Me Me Me field of the total synthesis. Me Me Seragamide A: (E)-284 (E/Z)-282 (Z)-284 1:1.2 mixture of separable isomers

Scheme 31 Total synthesis of seragamide A and related cyclodepsipeptides

2.3.3 Stereoselective Alkene Metathesis

The reversible nature of olefin metathesis represents a practically insurmountable barrier to access to the often energetically less favored Z-olefin. As a consequence, the design and development of catalysts capable of providing

high Z selectivity, either in RCM as in CM reactions, rep- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. resents an important challenge. To this aim, initial efforts by Schrock, Hoveyda, and co-workers have been focused largely on the modification of the ancillary ligands bound to the metal center and have led to the identification of the first Z-selective catalysts based on molybdenum and tungsten (catalysts 15–22 in Figure 1).156 In this family of catalysts, the introduction of a bulky aryloxy moiety forces the substituents on the generated metallacyclobutane intermediate A (Scheme 32) all syn to yield the Z-olefin in a kinetically controlled process. On the other hand, the advent of ruthenium-based catalysts (e.g., catalyst 23 in Figure 1), in which bulky aryl groups are introduced on the N-heterocyclic carbene, by Grubbs and co-workers, allowed similar ac- Scheme 32 Applications of Z-selective RCM reactions in total synthesis cess to a Z-selective process through intermediates type

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

Particularly relevant is the synthesis of prostaglandin An outstanding application of these selective catalysts F2α (303) according to the 2017 strategy developed by Hov- in the synthesis of complex natural products is the synthe- 163f eyda and co-workers (Scheme 33) based on the original sis of disorazole C1 (305), a secondary metabolite that dis- and brilliant concept of methylene capping. This strategy plays excellent anticancer and antifungal profiles, de- was designed to broaden the scope of the Z-selective cross- scribed by Hoveyda and co-workers (Scheme 34).164 The metathesis protocols, which are inefficient with olefins presence of the (Z,Z,E)-1,3,5-triene unit demands an exqui- containing allylic or homoallylic alcohols, aryl groups, alde- site level of geometric control for the stereoselective syn- hydes, or carboxylic acid substituents. Having identified thesis of this fragment. In an initial approach, they prepared (Z)-but-2-ene (302) as a suitable capping agent, respective the Z-vinyl iodide 307 and the E,Z-diene 309 in excellent treatments of trihydroxy olefin 300 and unsaturated car- yields and complete stereoselectivity by using the catalyst boxylic acid 301 with alkene 302 and the Ru dithiolate cata- 16 from the terminal olefins 306 and 308, respectively. lyst 25, followed by mixing and treatment with additional However, after coupling of both fragments via a Suzuki re- catalyst 25 under reduced pressure, afforded prostaglandin action, the subsequent dimerization process failed to form F2α (303) in 59% yield and >98:2 selectivity in favor of the the resulting coupling product. Therefore, they decided to desired Z-olefin. The use of this capping agent avoids the assemble the acid derived from ester 308 and vinyl iodide formation of the unstable methylidene species in favor of a 310 and the resulting ester 311 was transformed into the Z- more stable substituted carbene, allowing the use of sub- boronic ester 312, mediated by the catalyst 18. With this strates without resorting to protecting groups. This elegant compound in hand, they conducted the dimerization pro- strategy was similarly used for the synthesis of Z-macrocy- cess in a carefully optimized reaction, where the choice of clic alkenes. palladium catalyst, base, and solvent was critical to obtaining a good yield (60%) of the resulting [30]-membered ring Catalyst 23 AcO AcO protected disorazole C1. Final desilylation provided the cov- + Me 4 290 291 (30%) Pheromone 292 eted natural product 305. Me Me TBSO OTMS a) catalyst 16, B(pin) TBSO OTMS (72%, 98% Z) Catalyst 23 Me Me Me + b) I2, NaOH (79%) OAc Me Me Me Me I 8 (56%) OAc 293 294 306 307 Pheromone 295 MeO2C MeO2C N OMe N OMe B(pin) OTBS TBSO C7H15 OH C7H15 a) catalyst 16, B(pin) Catalyst 23 O (76%, 92% Z) O 308 309 TIPS C H TIPS 296 7 15 298 TBSO OH Falcarindiol (299) 297 2 steps Me OH (83%) Me Me I 310 HO 25, THF, 22 ºC O OMe O OMe CO2H C H Me Me 5 11 302 HO N N HO 25, 100 Torr 300 OH a) catalyst 18, B(pin) TBSO O O TBSO O O B(pin) 25, THF, 22 ºC (59%; C5H11 > 98:2 Z/E) (91%, 98% Z) HO Me Me CO2H Me Me OH 302 α Me Me I Me Me I 301 Prostaglandin F2 (303) 311 312

CONH2 OMe This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. HO Ph O O O O H H H N N N N BocHN N N NH H H O O O OH O O Me Me CO H Me Me 2 Me H N CM 2 NH Me Me Me (60%; 90% Z) Me Me NH2 NH O O OH b) [Pd], Cs2CO3 (60%) O O O Catalyst 4 H H H 3 H c) H2SiF6 (68%) N N N 23 BocHN N N N N H H O O O O Me Me 3NH MeO

Disorazole C1 (305) HN NH2 304 OH Scheme 34 Total synthesis of disorazole C1 Scheme 33 Applications of Z-selective CM reactions in total synthesis

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

2.3.4 Alkene Metathesis in Tandem Reactions O O H Grubbs II (4) TBSO O Ru O O The design of suitable multifunctional molecules that ROM O H TBSO 315 (84%) TBSO enable the triggering of a cascade of events, including a se- A 316 quential alkene metathesis process or a combination of an RCM Me O Me alkene metathesis with other types of reactions in a well- H H O defined order would provide a formidable increase in struc- H-G II (6) TBSO O TBSO O tural complexity in a single operation. As a consequence, OAc O MeOOC O (95%) AcO H H we can find in the literature a large number of total synthe- 317 318 167 ses and synthetic approaches in which alkene metathesis [Sasaki] [Sasaki]100 processes in cascade sequences, by combination of Me 165 OH HN ROM/RCM or RCM/CM reactions, have been applied. An H2N H H2N H O OH O OH initial interesting synthetic application of these processes HOOC HOOC HOOC O HOOC O in total synthesis is found in the formal total syntheses of H H dysiherbaine (313) and neodysiherbaine A (314) by Lee and Neodysiherbaine A (314) Dysiherbaine (313) co-workers (Scheme 35)166 through an elegant ROM/RCM Scheme 35 Formal total synthesis of dysiherbaine and neodysiher- tandem process from bicyclic compound 315, which was baine A prepared in enantiomerically pure form through a stereoselective Diels–Alder reaction, followed by resolution of the racemic mixture. This compound 315 underwent an initial when 322 was treated with the Grubbs II catalyst (4) in the ROM process that delivered a ruthenium intermediate A, presence of 2-methylbut-2-ene, the natural product clusia- followed by a RCM reaction when subjected to the Grubbs II none (319) was obtained in 65% yield as the result of a tan- catalyst (4) to yield bicyclic derivative 316, which rep- dem ROM/CM process. The preparation of the bicyc- resents the core skeleton of dysiherbaine and related com- lo[4.3.1]decenone derivative 321 via a RCM reaction from pounds with the correct relative stereochemistry. The need 320, was conceived by them as a way of controlling the ste- to selectively oxidize the cyclic olefin in the presence of the reochemical outcome in favor of the desired cis-relative terminal alkene found in compound 316 forced them to in- configuration of the final product due to the conformation- crease the difference of reactivities between the olefins by ally restricted environment imposed by the bicyclic system. the preparation of the enol acetate 317, prepared in the The subsequent ROM reaction, followed by a CM reaction, same way as 316, but in the presence of vinyl acetate and in the presence of 2-methylbut-2-ene, allowed the unmask- using H-G II catalyst (6) for a final CM with vinyl acetate. In ing of the prenylated side chains present in the final prod- this way, compound 317 was obtained in an excellent 95% uct (Scheme 36). The same strategy was employed by them yield, generating a very well differentiated electronic envi- in the synthesis of guttiferone A.169 For the clavilactones, a ronment between both alkenes for further selective func- family of natural products structurally characterized by a tionalization. In fact, they succeeded in the preparation of rigid 10-membered macrocycle fused to a hydroquinone advanced precursor 318 via transformation of the enol ace- and to an α,β-epoxy-γ-lactone, the cyclobutenecarboxylate tate into a temporary alcohol, followed by dihydroxylation 324 was devised by Takao and co-workers as an appropriate of the cyclic olefin, protection of the resulting diol as an ac- precursor to promote a tandem ROM/RCM reaction mediat- etal, oxidation of the primary alcohol to the acid, and esterification. The resulting product 318 was utilized by Sasaki 167 O O and co-workers (Scheme 35) in their total syntheses of O O O This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Grubbs II (4) MeO C the natural products dysiherbaine (313) and neodysiher- Me 2 CH2Cl2, 45 °C Me MeO baine A (314), thus representing the formal synthesis of Me Me (73%) Me (4 steps) both natural products. Me Particularly interesting are the syntheses of clusianone 320 321 (319) and clavilactone A (323) which utilize combinations of cascade processes of metathesis reactions. In the case of O O Grubbs II (4) clusianone (319), a natural product isolated from C. conges- Me HO O Me 2-methyl-but-2-ene HO O O O CH2Cl2, 45 °C tiflora with antiviral activity against HIV and Epstein-Barr Me Me Me (65%) virus, its synthesis was envisaged by Plietker and co-work- cis 168 Me Me ers (Scheme 36) from tricyclic derivative 322, prepared Me from bicyclic compound 321 via an allylation/intramolecu- 322 Me Me lar Claisen condensation/benzoylation sequence. Thus, (+)-Clusianone (319) Scheme 36 Total synthesis of clusianone

Syn thesis I. Cheng-Sánchez, F. Sarabia Review ed by a ruthenium-based catalyst (Scheme 37).170 In fact, tion employed by Krische and Waldeck in the synthesis of when 324 was treated with the Grubbs I catalyst (3), the the C2-symmetric natural product cyanolide A (332) desired ROM/RCM product 325 was obtained, but in only (Scheme 38),172 a potent molluscicidal agent against the 28% yield, due to the formation of the dimer 326 in 15% water snail Biomphalaria glabrata, which actually is a vec- yield, together with recovered starting material in 47% tor of the human parasitic disease schistosomiasis. Thus, yield. In an attempt to improve upon this modest result, treatment of diol 333 with H-G II catalyst (6) in the pres- they found that exposure of dimer 326 to the Grubbs II cat- ence of pent-1-en-3-one gave compound 334 in 76% yield alyst (4) in ethylene atmosphere produced the desired as a 10:1 mixture of diastereomers. This pyran derivative is product 325 in good yields. In practice, this tandem process the result of an initial double CM reaction, followed by an was accomplished in one pot by sequential treatment of oxa-Michael cyclization. In a second CM round, compound 324 with the Grubbs I catalyst (3) in the presence of 2,6-di- 334 was treated with the Blechert catalyst 7 in an ethylene chloro-1,4-benzoquinone, followed by the treatment with atmosphere to yield olefin 335 in 70% yield. A few more the Grubbs II catalyst (4) in atmospheric ethylene at 80 °C steps from 335 completed a concise total synthesis of cyan- to provide the final product 325 in 81% overall yield. The olide A (332) (Scheme 38). formation of the oxirane ring was carried out in a highly chemo- and stereoselective fashion by reaction of mCPBA COEt Me b) Blechert catalyst (7) with the cyclic olefinic bis-silyl ether derivative, obtained OH OH Me a) H-G II (6) OH ethylene from 325 by reduction and bis-silylation of the resulting di- O O (70%) ol. The resulting epoxide 327 was then reacted with the Me Me (76%) 333 O Grubbs II catalyst (4) to obtain the macrocyclic derivative Me Me Me tandem CM/oxa-Michael OH 328 in a notable 83% yield. The completion of the synthesis Me of clavilactone A (323) was efficiently accomplished in four Me 334 O O additional steps, mainly functional groups interconver- O O Me Me OMe sions, through quinone 329 that corresponds to clavilactone MeO O O O OMe Me B. In a similar synthetic sequence, they prepared the origi- 335 MeO O O O OMe (6 steps) nally proposed structure of clavilactone D (330) (Scheme OMe Me Me O O 37),171 which led to its structural revision, identifying 331 as the correct structure. Me Cyanolide A (332) Me OMe OMe OMe Scheme 38 Total synthesis of cyanolide A Br Grubbs I (3), toluene Br 80 °C; then (4 steps) Grubbs II (4) Another such application is the synthesis of the tetrahy- ethylene, 80 °C O OMe O OMe O OMe O dropyran-containing natural products decytospolide A (81%) Si O 324 ROM/RCM 325 O tBu (336) and B (337) by Kommu and co-workers (Scheme O tBu 327 173 OMe O Grubbs II (4) 39), which was rapidly achieved when the hydroxy olefin Br O OMe ethylene Grubbs II (4) (83%) 338 was subjected to treatment by the H-G II catalyst (6) in 2 Me OMe the presence of pent-1-en-3-one to provide the pyrans 339 OMe O 2 Br and 340 in 78% combined yield and as a 9:1 mixture of ste- O 326 OMe reoisomers, in favor of the desired 2,6-cis-pyran 340. Re- Me O O OMe O O HO t Si Bu This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Originally proposed tBu Clavilactone D (330) 328 BnO O O a) TBAF c) CAN O O Me O b) TPAP, NMO (58% over Me O H H 3 steps) OBn a) H-G II (6) Me Me 339 Me Me DCE, 80 °C O OH O + O BnO OH O d) NaBH4 Me 338 Me H N (79%) (78%) Me O 2 O O O H H O O OH O O O O O O 340 Revised Clavilactone D (331) Clavilactone A (323) Clavilactone B (329) b) DDQ Scheme 37 Total synthesis of clavilactone A, B, and D (94%) AcO HO O c) Ac2O, pyr O Me Me Me O (82%) Me O A cascade process that involves an alkene metathesis Decytospolide B (337) Decytospolide A (336) with other types of reactions has also been explored. As such, an application is the tandem CM/oxa-Michael cycliza- Scheme 39 Total synthesis of decytospolide A and B

Syn thesis I. Cheng-Sánchez, F. Sarabia Review moval of the benzyl group of 340 afforded decytospolide A enyne-metathesis (RCEYM) reaction has been similarly cov- (336), whose acetylation provided decytospolide B (337) ered in numerous reviews.176 (Scheme 39). An interesting approach towards the synthesis of iso- 3.1 Total Syntheses Based on a Ring-Closing quinoline-type alkaloids, such as oxychelerythrine (341a), Enyne-Metathesis Reaction oxysanguinarine (341b), oxynitidine (341c), and oxyvicine (341d), has been described by Sutherland and co-work- The synthetic value of an intramolecular metathesis re- ers174 based on a tandem Overman rearrangement/RCM for action of an enyne (RCEYM) is due to the versatility that is rapid access to amino-substituted 1,4-dihydronaphthalene offered by the resulting cyclic dienes, which can be utilized scaffolds, which represent key precursors for the synthesis in subsequent transformations, such as cycloaddition reac- of the benzo[c]phenanthridine system found in these natu- tions. On the other hand, in contrast to other metathesis ral products (Scheme 40). The one-pot Overman rearrange- processes, the enyne metathesis can be promoted by other ment/RCM was efficiently achieved after extensive optimi- metal catalysts, such as Pt2+, Pt4+, or Ir, or even Lewis acids, zation, finding that when 342 was converted into the corre- by a different mechanism, but with the same result. Inter- sponding trichloroacetimidate, heated to 160 °C in the estingly, in contrast to the alkene RCM, for the enyne RCM, presence of potassium carbonate and then submitted to the the mode of the ring closure can be different depending on action of the Grubbs II catalyst (4) at room temperature, the the size of the cyclic system.177 Thus, whereas in small- and corresponding 1,4-dihydronaphthalene 343 was obtained medium-sized rings, the cyclization pathway goes through in 81% yield. From this privileged compound, they complet- an exo-mode that delivers the product type A, in a macro- ed the syntheses of the alkaloids 341a–d, after aromatiza- cyclization process, the ring closure can go through an tion of 343, followed by coupling with the corresponding 2- endo-pathway, owing to the increased flexibility of the bromobenzoic acid derivatives, and an intramolecular bi- large ring system, that should afford the product type B. A aryl Heck coupling reaction, in a very highly efficient man- clear example of the formation of this class of type B com- ner. In the final Heck coupling (step h of the sequence), pounds is the synthesis of 6-deoxyerythronolide B (345) by Sutherland and co-workers employed the more stable Her- Krische and co-workers (Scheme 41),178 who prepared mac- mann–Beller palladacycle catalyst, given the very high tem- rocyclic 347 in 89% yield when the enyne 346 was treated perature (160 °C) required for the intramolecular coupling with H-G II catalyst (6) in an atmosphere of ethylene at 110 of their precursors 344a–d (Scheme 40). A related tandem °C, with no detection of regioisomers. With the formation Overman rearrangement and ring-closing enyne metathe- of the 14-membered macrocycle, the completion of the sis, followed by a Diels–Alder reaction was utilized by them synthesis of the deoxyerythronolide B (345) was delineated in the synthesis of amino-substituted indanes and tetra- through a synthetic sequence that included selective oxida- lins.175 tion of the exocyclic double bond, reduction of the resulting enone through a Ni-catalyzed conjugate reduction, stereo- O a) Cl3CCN, DBU selective methylation of the resulting ketone 348, and final O b) K CO , 160 °C 2 3 O removal of the protective groups via catalytic hydrogena- d) MnO O c) Grubbs II (4), r.t. HN O 2 one-pot e) HCl, MeOH tion (Scheme 41). Given the usual involvement of the enyne 342 OH 343 (81%) CCl3 f) ClCOAr RCM products in subsequent transformations of the result- DIPEA [Pd] = Hermann-Beller palladacycle catalyst (63% over ing diene in a tandem process, the majority of cases found 3 steps) in the literature correspond to this category and will be dis-

O g) MeI, NaH O cussed later in Section 3.3. Br 1 h) [Pd], Ag CO 1 O R 2 3 O R This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. HN (78–95%) HN 3.2 Total Syntheses Based on an Enyne Cross-Me- R2 R2 O R3 O R3 tathesis Reaction Oxychelerythrine (341a) 344a: R1 = H, R2 = R3 = OMe Oxysanguinarine (341b) 1 2 3 344b: R = H, R + R = OCH2O Several problems are associated with the selectivity of Oxynitidine (341c) 344c: R1 = R2 = OMe, R3 = H 1 2 3 Oxyavicine (341d) 344d: R + R = OCH2O, R = H an intermolecular enyne metathesis, for example alkene- Scheme 40 Total synthesis of oxybenzo[c]phenanthridine alkaloids alkene and alkyne-alkyne metathesis processes can compete with the alkene-alkyne coupling, as well as the possible formation of geometric E/Z mixtures. Indeed, these 3 Enyne Metathesis in Total Synthesis problems are the likely reasons for the limited use of this modality of metathesis versus the intramolecular variant. As in previous sections, in this section we will focus on Due to the scarcity of examples in which an enyne cross- recent contributions recorded in the last few years (2012 to metathesis is employed in the realm of total synthesis, it is early 2018), taking into account that the ring-closing worth emphasizing those where the reaction has been suc-

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

Ru HF·pyridine in 67% yield over two steps (Scheme 42). This exo-mode contribution joins the synthesis by Lee and co-workers [For small and 181 medium-sized rings] n n based on an RCM approach. A Ru [Ru] Me

n n O O Ru a) H-G II (6) OH Me toluene, –20 °C TBSO TBSO [For macrocycles] E/Z = 4.5:1 O Me O Me endo-mode CO2Me CO2Me Me 350 OH 351 Me 352 n n (72%) B b) 125–130 °C, toluene (38% overall c) TBAF yield) Me Me R Me Me Me Me OBn a) H-G II (6) OBn Me O O Me ethylene, 110 °C Me Me O O O O Me enyne RCM (89%) TBSO Me Me O O PMP O O PMP O O O O Me Me Me O 346 347 O OH b) OsO4, NMO Me Me (50% over then NaIO 354: R = SiMe Amphidinolide P (349) 4 2 steps) 3 c) NiCl2, NaBH4 353: R = H O O a) Grubbs II (4) c) Grubbs II (4) toluene, 110 °C (67% over Me Me Me ethylene, CH2Cl2, r.t. d) HF•pyr 2 steps) d) LHMDS, MeI (99%) Me Me Me Me OBn e) H2, Pd(OAc)2 OBn Me (79% over 2 steps) Me Me O O O O OH Me Me Me Me b) TBSOTf, DIPEA O O PMP TBSO O O OH TBSO O O Me Me O O (92%) Me Me 6-Deoxyerythronolide B (345) 348 O Scheme 41 Different pathways of the ring-closing enyne metathesis Me 355 OTBS 356 and total synthesis of 6-deoxyerythronolide B Scheme 42 Total synthesis of amphidinolide P cessfully applied. Such a case is the synthesis of amphidino- 3.3 Enyne Metathesis in Tandem Reactions lide P (349) by Diver and Jecs (Scheme 42),179 in which an enyne cross-metathesis allowed access to the main back- Among the different variants of the metathesis reac- bone of the natural product. In practice, alkyne 350 and tions that employ enynes as starting precursors, those that alkene 351 were coupled by treatment with the H-G II cata- involve the enyne metathesis as part of a cascade process lyst (6) at low temperature (–20 °C) to give diene 352 in 72% have been the most exploited, due to their great potential yield and as a 4.5:1 E/Z mixture of geometric isomers. The for the generation of complex polycyclic systems in a single completion of the synthesis was achieved according to the step. Given the synthetic consequences of such processes, Williams protocol180 to obtain pure amphidinolide P (349) enyne metathesis in cascade processes has occupied a stra- in 38% overall yield. Surprisingly, when they attempted the tegic position in the synthesis of natural products contain- synthesis of this natural product via an enyne RCM, they ing complex polycyclic systems and has been the topic of 182 failed to obtain any ring-closure product, either from 353 or several comprehensive reviews. One finds two well-dif- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. from the more stable TMS derivative 354. However, when ferentiated types of tandem processes involving enyne me- 353 was subjected to the Grubbs II catalyst (4) in an eth- tathesis: (a) Multiple intramolecular metathesis reactions ylene atmosphere, they could obtain, in almost quantitative in a programmed polyenyne system. In this case, the poly- yield, the 1,3-diene 355, which was envisioned as a suitable enyne precursor is properly designed to trigger a highly or- precursor for a final RCM step. In this case, they observed chestrated cascade that ensures the correct regiochemical that the RCM reaction of its corresponding silyl enol ether, outcome, once the initial metal carbene is formed in the compound 356, with the Grubbs II catalyst (4) proceeded in correct position. (b) A tandem process consisting of an ini- a better yield, compared with the direct RCM reaction of tial enyne ring-closing metathesis, followed by a second re- the diene 355, likely due to the introduction of additional action, usually a cycloaddition reaction, of the resulting di- rigidity in the system that would favor the connection of ene. In the first case (a), we find a relevant example in the the involved alkenes. The RCM product, obtained as a mix- formal synthesis of englerin A (357) by Parker and Lee ture of the corresponding silyl enol ether and ketone, was (Scheme 43).183 The intriguing structure of this natural transformed into amphidinolide P (349) by reaction with product, in conjunction with its striking pharmaceutical

Syn thesis I. Cheng-Sánchez, F. Sarabia Review properties, has prompted intense research activity directed rivative 363 in an astonishing 97% yield. Whereas the re- towards its total synthesis, as well as the generation of ana- duction of the resulting tetracyclic ketone 363 with L-Selec- logues for medicinal chemistry studies. tride provided the alcohol 364 with the opposite stereochemistry to that of the natural product, reduction of the bicyclic ketone precursor 362 provided the correct diaste- Me O Me Ru Me Ru Me reomer 365 under the same reduction conditions. In a simi- Me Grubbs– Me Me Me Me Stewart (12) lar way as for 362, dienyne 365 was subjected to treatment (77%) by the Grubbs II catalyst (4) to obtain the tetracyclic alcohol Me O Me O Me O 366 in almost quantitative yield (99%). From this com- OO O O pound, the synthesis of the kempenone 361 was achieved A B O 358 O in nine additional steps (Scheme 44).

Ph O Me Me Me Me Me Me Me Me O Me Me OH Me Me Me H Me a) Grubbs II b) L-Selectride Me (4) Me H (73%) Me H O O Me Me Me O (3 steps) (97%) Me H Me H (7 steps) H Me H O Me O [Echavarren]184 Me OTBS O O O HO Me OH H H H Englerin A (357) 360 359 O 362 363 364 Scheme 43 Total synthesis of englerin A (92%) c) L-Selectride

Me Me Me Me Me Among the seminal and elegant contributions devel- O oped for the synthesis of this natural product, the one by Me a) Grubbs-II Me H Me H Me (4) Me Me Parker and Lee was based on a ene-yne-ene metathesis cy- Me Me H Me H (99%) HO HO (9 steps) HO clization in a tandem process. In order to secure the initia- H H H tion process in the correct direction, they developed a relay 365 366 3β-hydroxy-7β-kemp- metathesis cascade from precursor 358, in form of a diaste- 8(9)-en-6-one (361) reomeric mixture, which was readily available from gerani- Scheme 44 Total synthesis of kempenone ol in seven steps. Thus, when compound 358 was treated with the Grubbs–Stewart catalyst (12), the expected tricy- Yet another instructive example for this section is the clic derivative 359 was obtained in 77% combined yield of elegant synthesis of (±)-morphine (367) by Smith and co- both stereoisomers, which could be separated by chromato- workers (Scheme 45),187 in which the intricate pentacyclic graphic methods. The power of this tandem metathesis re- system contained in this fascinating natural product was action is reflected by the fact that only the guaiadiene sys- generated utilizing a cascade ene-yne-ene ring-closing me- tem was generated in a strict order of events through ru- tathesis of the highly functionalized benzofuran 368, pre- thenium carbene species A and B due to the triggering pared in just six steps from commercially available starting effect exerted by the terminal allyl ether. The formation of materials. In the crucial metathesis event, the catalytic ac- the oxygen bridge present in the natural product was then tion of the H-G II catalyst (6) smoothly promoted a sequen- accomplished by means of an oxymercuration and subse- tial cascade of events, initiated with an enyne-RCM reac- quent demercuration process that afforded the advanced tion, that generated the ruthenium alkylidene intermediate intermediate 360. The transformation of this compound A, and continued with a final RCM reaction to produce tet-

into englerin A (357) has already been described by Echa- racyclic compound 369. Despite this product being isolated This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. varren in seven steps (Scheme 43).184 in an impressive 94% yield, they decided to continue with Another representative and unique example is the syn- the synthetic sequence without isolation of the resulting thesis of the complex tetracyclic diterpenes belonging to tetracycle 369. The compound was then subjected to a 1,6- the kempene family, such as the kempenone 361, which addition reaction by treatment with TFA and then sodium was isolated from the defense secretion of higher termites carbonate. As a result, a 10:1 mixture of compounds corre- Nasutitermes octopolis. In contrast to the long multistep ap- sponding to neopinone (370) and codeinone (371) was ob- proaches reported by Paquette and Deslongchamps for the tained. The treatment of this mixture with HCl, followed by construction of the tetracyclic core of these terpenes,185 NaOH workup, allowed for the isomerization of neopinone Metz and co-workers reported the preparation of this poly- (370) to codeinone (371). The reduction of 371 with sodi- cyclic system in one step and in excellent yield from the di- um borohydride afforded codeine (372) as a single diaste- enyne 362 (Scheme 44), which was prepared from the reomer in 65% overall yield from 368. Finally, demethyla- Wieland–Miescher ketone in 20 steps.186 Thus, exposure of tion of codeine with boron tribromide yielded racemic 362 to the Grubbs II catalyst (4) afforded the tetracyclic de- morphine (367) in 86% yield (Scheme 45).

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

Me Boc Boc iboidine (374), after a final lactamization reaction of 373 Me N N Me N Boc with EDC (Scheme 46). a) H-G II Ru With regards to recent examples, special attention is de- O (6) MeO MeO served for the synthesis of the anticancer alkaloids flueg- O CH2Cl2 O O 20 °C H H gine A (378) and virosine B (379) by Li, Yang, and co-work- OMe O O 368 A 369 ers (Scheme 47).189 These compounds, belonging to the se- b) then TFA curinega family, possess unique structural features and then Na2CO3 interesting biological properties that cover a wide range of Me Me Me N N N activities. The synthesis of these compounds was based on H H c) then NaBH4 an elegant RRCM of a dienyne system for the controlled RO MeO + (65% over MeO construction of the core structure represented by norse- O 3 steps) O O curinine (385). Thus, their syntheses were envisioned to H H H OH O O proceed via a 1,3-dipolar cycloaddition between norse- b) BBr3 Codeine (372): R = Me Codeinone (371) Neopinone (370) (86%) Morphine (367): R = H HCl; then NaOH curinine (385) and nitrone 386, which would be prepared from norsecurinine (385) by oxidative treatment with mCP- Scheme 45 Total synthesis of (±)-morphine BA. In a similar strategy towards the related alkaloid securinine, Honda and co-workers (Scheme 47)190 attempted An interesting example of the synthetic application of its synthesis through a tandem RCM of the dienyne 380. domino metathesis in the field of the alkaloid-type natural However, when this precursor was reacted with different products is the recent syntheses of virgidivarine (373) and ruthenium catalysts, such as the Grela–Grubbs–Hoveyda virgiboidine (374), which are piperidine and piperidino- catalyst (10), the desired γ-lactone 381 was not detected, quinolizidine alkaloids isolated from the leaves of African obtaining instead the δ-lactone 382 in 69% yield. The pref- leguminosae Virgilia divaricata and Virgilia oroboides and erence of the catalyst to react with the butenyl group rather whose biological activities have not been studied. Blechert than the acrylate moiety, through intermediate A, could ex- and co-workers (Scheme 46)188 planned the construction of plain the outcome of this reaction. In an attempt to favor the common dipiperidine core of these natural products via the formation of the required ruthenium complex at the a ene-ene-yne ring-rearrangement metathesis (RRM) from less reactive alkene, Li, Yang, and co-workers189 proposed the dienic system represented by compound 375, foresee- the trienyne 383 (Scheme 47) as a suitable precursor to ing an initial ROM process of the cyclopentene unit, fol- promote the preferential formation of intermediate C lowed by a double alkene RCM-enyne RCM process of the through the initiation of the reaction at the less sterically resulting ROM intermediate. Thus, when precursor 375, encumbered terminal olefin. In fact, when compound 383 prepared from cis-cyclopent-2-ene-1,4-diol via enzymatic was subjected to the action of the Zhan-1 b catalyst (11), desymmetrization, was exposed to the H-G II catalyst (6) among others, compound 384 was obtained in a reproduc- under ethylene atmosphere, compound 376 was obtained ible and acceptable 64% yield. The completion of the syn- in a remarkable 83% yield, according to the expected mech- thesis of norsecurinine was undertaken in three additional anistic course delineated by them. Combined with the tan- steps, allylic bromination, Boc deprotection, and a nucleop- dem metathesis reactions, the resulting metathesis product hilic cyclization under basic conditions. After some addi- was transformed into the aldehyde 377 by oxidative treat- tional experimentation, they found that this transformation ment in 33% overall yield in one pot. From this aldehyde, could be achieved in only one step by exposure of the re- both alkaloids were prepared, requiring ten steps to synthe- sulting bromide to the acid AgSbF6 in an improved 85%

size virgidivarine (373), followed by the synthesis of virg- yield. Finally, the preparation of the nitrone 386 from nor- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. securinine (385), according to the Magnus protocol,191 was followed by a cycloaddition reaction with 385 to obtain alkene RCM natural product flueggine A (378) in 77% yield. In a related Boc b) AD-mix β N a) H-G II (6) c) NaIO4/SiO2 approach, they also prepared virosaine B (379) by an intra- N N Boc molecular cycloaddition of nitrone 388, prepared from the ROM (83%) Nos N Nos (33% overall one-pot isomer allonorsecurinine (387) in three steps (Scheme 47). ene-yne RCM from 375) from 375 376 375 In the second group of the cascade reactions involving enyne-RCM processes, we wish to highlight those that com- N EDC, NMM COOH bine the metathesis reaction with a Diels–Alder cycloaddi- N N O N (29%) H Boc tion of the resulting diene as a way for the construction of a N (10 steps) N O Nos bicyclic system in a rapid and efficient fashion. Within this Virgiboidine (374) 377 Virgidivarine (373) category of tandem reactions, the synthesis of the norsesquiterpene-type alkaloids, such as the anticancer alkaloid Scheme 46 Total synthesis of virgidivarine and virgiboidine

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

O O O MeO O Grela–Grubbs– OBn OBn MeO C O Hoveyda (10) O O Me Me a) Grubbs I (3) 2 Me H H H (69%) Me then Me Me MeO C CO Me NBoc NBoc Ru NBoc 390 2 2 391 380 A 382 (DMAD) [Honda, 2004]190 then DDQ (42%) O O Ru O b) aq. KOH MeO O O O HN H H OH c) Urea, ethylene glycol OBn MeO C O Me d) H2, Pd/C 2 Me NBoc NBoc Me Me (49% over 3 steps) Me Me B 381 389 392 O Me Me Scheme 48 Total synthesis of the norsesquiterpene alkaloid H H a) Zhan-1 b (11) O Me Me H N (64%) N Boc O Boc O Ru NBoc tunities. Thus, some advantages of alkynes over alkenes in- O O 383C 384 clude the stereocontrolled partial reduction of the triple b) NBS, AIBN bond, which allows stereoselective access to the E- or Z- c) AgSbF6 (51%) O alkene, and its excellent reactivity against electrophilic O O d) mCPBA, MeOH O metals such as Ag, Pt, or Hg, which allows for further func- O H H e) reflux H O g) 385 O O H f) mCPBA, CH2Cl2 H tionalization. On the other hand, the catalysts required for N N O reflux (74%) the alkyne-metathesis reactions are completely different. H (77%) N N 193 O OH From the first Mortreux system developed in 1974, the HO norsecurinine evolution towards more efficient, stable and functional Flueggine A (378) 386 (385) group tolerant catalysts, developed first in 1982 by Schrock O O O (393)194 and later in 1999 by Fürstner (394)195 (Figure 7), O a) mCPBA, MeOH O O H b) reflux H H H has propelled the alkyne-metathesis reaction to become an c) mCPBA, DCE HO excellent synthetic tool for the generation of macrocyclic N AcOH N H H structures as applied to the synthesis of natural products (62% overall O OH H O N allonorsecurinine yield) and bioactive compounds. Since the first example of an (387) 388 Virosaine B (379) alkyne ring-closing metathesis in 1999 by Fürstner,196 we Scheme 47 Total synthesis of flueggine A and virosaine B can find in the literature many applications of this type of reaction in the preparation of complex macrocyclic natural 389, which were isolated from the culture of mushroom- products, some of the which have been linked to the devel- forming fungus Flammulina velutipes, was accomplished opment of even more efficient and stable catalysts (395– using a tandem enyne-RCM/Diels–Alder/aromatization se- 399) since 2011.197 As for the catalysts used in alkene me- quence in one-pot by Reddy and co-workers (Scheme tathesis, the catalysts for alkyne metathesis are precata- 48).192 Thus, the treatment of the acyclic precursor 390 with the Grubbs I catalyst (3) in toluene at 50 °C was followed by a Diels–Alder reaction with dimethyl acetylenedi- Me Me N OtBu OMe t t carboxylate and then, treatment with DDQ of the resulting BuO O Bu Mo OSiPh3 tBu Ph3SiO W N Diels–Alder adduct 391, which was not isolated, to provide Me N N Ph3SiO Mo tBu 396 the final compound 392 in a moderate 42% overall yield. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 197 t N Me [Fürstner, 1999] The elaboration of this product towards the final alkaloid Me Me Bu Mo Ph3SiO Me Me OSiPh3 389 was accomplished without issues in three additional 393 394 Ph3SiO 395 Me steps in 49% overall yield (Scheme 48). [Schrock, 1982]194 [Fürstner, 1999]195 [Fürstner, 1999]197

OMe N NMo N 4 Alkyne Metathesis in Total Synthesis K Me Me Mo OSiPh Ph SiO 3 Me 3 Ph SiO OSiPh 4.1 Total Syntheses Based on a Ring-Closing OSiPh3 3 3 Me Ph3SiO Mo Me Me N Alkyne-Metathesis Reaction 397 Ph3SiO 399 [Fürstner, 1999]197 N [Fürstner, 1999]197 The wide range of reactivities that alkynes possess, 398 compared with alkenes, imparts alkyne metathesis as a [Fürstner, 1999]197 very powerful tool with a broader field of synthetic oppor- Figure 7 Common catalysts used for alkyne-metathesis reactions

Syn thesis I. Cheng-Sánchez, F. Sarabia Review lysts, which are activated to form the active species respon- representative cases, the alkynes were reduced to the cor- sible for catalytic action. In fact, precatalysts 394 or 399 are responding E-alkenes (cases of natural products 400, 403, activated by reaction with CH2Cl2 to form in situ the corre- and 405), Z-alkenes (cases of 401 and 404), or even, not sponding monochloro derivatives, which are the catalyti- transformed, such as the cases of the 4-pyrone 406. For the cally active species.198 One of the main architects of the re- particular case of amphidinolide F (402), the alkyne was sponsible for the spectacular irruption of this reaction in subjected to a hydration reaction to obtain a ketone under modern organic synthesis has been Fürstner, who by both platinum catalysis. Similarly relevant are the syntheses of his seminal contributions in total synthesis and his work on WF-1360F (413),207 cruentaren A (31),208 and haliclonin A the development of new catalysts has reached spectacular (414),209 reported by the Altmann, Barrett, and Huang progress and promoted the field. During his prolific and im- groups, respectively, in which after the alkyne macrocycle pressive research career, many reviews have been reported formation via a RCAM reaction, the resulting macrocyclic about this reaction covering the main contributions of the alkynes 415–417 were reduced to the E-olefin in the case of Fürstner group as well as of other groups.199 The contribu- 415 or to the Z-olefins by means of a Lindlar catalyst medi- tions reported in the period 2015–2017, however, have not ated hydrogenation for 416 and 417 (Scheme 50). been covered and thus will be reviewed in this section. More intriguing and challenging are the cases in which Thus, selected examples are illustrated in Scheme 49, in the introduction of a methyl group into the alkyne is re- which the natural products lactimidomycin (400),200 man- quired to be transformed into a methyl-branched alkene in delalide A (401),201 amphidinolide F (402),202 brefeldin A a regio- and stereocontrolled manner. Such cases can be (403),203 leidodermatolide (404),204 tulearin A (405),205 or found in the synthesis of the natural products 5,6-dihydro- brominated 4-pyrone-type natural products206 (e.g., 406) cineromycin B (418), disciformycin B (419), and nannocys- were efficiently synthesized from their corresponding acy- tin Ax (420) by the Fürstner group. To this aim, the recent clic dialkynes which gave the corresponding alkyne macro- methodology developed by this group, based on the ruthe- cycles 407–412 in good to excellent yields. In the depicted

RCAM Catalyst Me Me (85%) 397 O H H H H O OTBDPS O OH Me OBz OTES HN OH O OH O OH O O O Me O O O O O (5 steps) Me Me Me Me Me RCAM Me (72%) 407 Lactimidomycin (400) O O Catalyst OTES RCAM Catalyst O 395 (73%) 395 O OTBS Me O O (5 steps) Me Me Me Me 408 OTBS OH HO OMe H O Me H O Me Me OTBS Me OH OH H H H H H H Mandelalide A (401) O O Me O O Me RCAM (72%) Catalyst OTBS O OH O TBSO 399 Me Me Me Me 409 Amphidinolide F (402) MOMO I Me O OTBS OH Me (5 steps) a) H2, [Cp*Ru(MeCN)3]PF6 H O O This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. O Me O H N O TBSO (56%) 411 2 O Me HO Me b) aq. HCl, THF O (94%) H Me Me Me RCAM OH HO (67%) Brefeldin A (403) Me Me Catalyst 410 395 O O O Me Br Me Catalyst Me Me O O 395 Me Leiodermatolide (404) Me Me O O RCAM Br (96%)

O O Me O O Me (4 steps) RCAM Catalyst (82%) OR RO OH HO 395 Me Me O 406

OTES O NH2 Me Me 412: R = TBS Tulearin A (405)

Scheme 49 Selected natural products synthesized via a RCAM reaction by the Fürstner Group (2013–early 2018)

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

Me Catalyst Me trans-hydrostannation reaction. In contrast to the previous RCAM O O 398 O O case, as to other numerous examples carried out by the (69%) (5 steps) Fürstner group, on this occasion a 3:1 mixture of stannyl O TIPSO HO regioisomers, in favor of 423, was obtained, likely due to Me Me Me O O the competing interactions of the hydroxy group, via hy- Me N Me Me I O O O drogen bonding, with the ruthenium catalyst and with the Me Me neighboring ester carbonyl group. In addition to this lack of OMe OMe 415 WF-1360F (413) regioselectivity, the observation that the stannyl derivative [Altmann, 2013]207 Me OTBS Me OH was quite sensitive forced them to continue with the crude

OMe O OPMB OH O NH product mixture to the following step, which consisted of a Me (7 steps) Me Me O O O OH RO RCAM MeO OH RCAM OTBS (75%) (92%) Me Me a) HF•pyr (84%) TIPSO Me Catalyst HO Me Catalyst Me Me b) Bu3SnH, [Cp*RuCl2]n, (83%) 416: R = Me 396 Cruentaren A (31) 397 OTES OH [Barrett, 2012]208 Me c) [Pd(PPh3)4], [Ph2PO2][NBu4] Me CuTC, MeI (92%) Me O O Me O O PhO2S OHC N HO H N 421 5,6-Dihydrocineromycin B (418) TBSO H Me Me (7 steps) O O Me a) AgF, HOAc Me O O O O b) HCOOH O O N N Me O Me O RCAM O TMS SnR3 O c) Bu SnH (70%) Me 3 Me Me O [Cp*RuCl] Me O Catalyst (–)-Haliclonin A (414) 4 417 TBSO TBSO 398 [Huang, 2016]209 Catalyst RCAM (90%) 399 423 (R = Bu) + several byproducts 422 Scheme 50 Selected natural products synthesized via a RCAM reaction Me d) [(cod)Pd(Me)Cl] (20% over 4 steps) by other research groups (2013–early 2018) O Me Me O O O Me O Me Me Me (3 steps) O O nium-catalyzed trans-hydrostannation of alkynes, was en- Me O Me O Me O Me visioned as a solution to this synthetic problem given the O Me O excellent levels of regioselectivity exhibited by this reaction OH TBSO HO 424 OH when applied to unprotected propargyl alcohol derivatives. Disciformycin B (419) Thus, in the case of 5,6-dihydrocineromycin B (418) Cl Cl OR (Scheme 51),210 when alkyne 421, smoothly obtained from OR Me Cl Me Cl the corresponding acyclic dialkyne by reaction with the O OTBS O OH H H N Me N Me molybdenum alkylidyne complex 397, was desilylated by Me N Me N H Me a) HF•pyr (71%) H Me reaction with HF, the resulting propargyl alcohol was treat- O NMe O O NMe O O O O O b) Bu3SnH ed with Bu3SnH in the presence of the ruthenium catalyst [Cp*RuCl ] Me Ph 2 n Me SnBu3 (80%) Ph [Cp*RuCl2]n. As a result, the corresponding α-alkenylstan- Me Me Catalyst nane was obtained as a single isomer. Having introduced OTBS RCAM (66%) OH 395 the stannyl group, a Stille reaction was carried out by expo- 425 (R = Phenacyl) 426 (R = Phenacyl) sure to copper thiophene-2-carboxylate (CuTC), [Ph2- OMe c) [Pd(PPh3)4], [Ph2PO2][NBu4] e) Zn, AcOH This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. CuTC, MeI (70%) (44% over PO2][NBu4], and Pd(PPh3)4 in the presence of methyl iodide O d) 427, Ph3PAuCl, AgOTf 2 steps) to afford the final natural product 418 in excellent yield. It Cl is important to highlight the importance of the order of ad- C H OH 427 4 9 dition and stoichiometry of the reactants in this reaction to Me Cl O OH H avoid undesired protodestannation processes. In a similar N Me 211 Me N situation, the macrocyclic alkyne 422 (Scheme 51), ob- H Me O NMe O tained in excellent yield from its corresponding dialkyne O O Me Me precursor by reaction with precatalyst 399, required the in- Ph stallation of the methyl group for the synthesis of discifor- Me mycin A and B, interesting macrolides-type antibiotics with OMe Nannocystin Ax (420) considerable activity against resistant Gram-positive bacte- ria. As the previous case, the transformation of compound Scheme 51 Selected natural products synthesized via RCAM/hydros- 422 into its hydroxy derivative was followed by a rapid tannation reactions by the Fürstner group

Syn thesis I. Cheng-Sánchez, F. Sarabia Review methylation reaction. Once again, this reaction proved to be by a sequence of redox isomerization, followed by transan- sluggish, as a mixture of products was obtained under con- nular aza-Michael addition from macrocyclic alkyne 435 ventional conditions. (Schemes 52 and 53). In light of these unsatisfactory results, they decided to Me use stoichiometric amounts of the methyl donor MeO Me MeO [(cod)Pd(Me)Cl] to obtain the desired product 424 in 20% Me Me O N N overall yield after four steps from 422. Final glycosidation O O O O and global deprotection provided the elusive disciformycin Me O a) Zn, HOAc Catalyst OTBDPS B (420) in the first instance, and then disciformycin A after 397 Me b) 436, AgSbF6 Me OTBDPS RCAM (85% over AcO an isomerization reaction. Similarly challenging proved to Me (79%) 2 steps) be the synthesis of nannocystin Ax (420) (Scheme 51),212 a O cytotoxic cyclodepsipeptide isolated from myxobacteria. AcO OTroc After a successful alkyne RCM reaction that provided mac- 432 c) K2CO3, MeOH e) (FmO)2PN(i-Pr)2 439 d) NaBH4 then H2O2 rocyclic alkyne 425 in 66% yield by the action of catalyst q) TBAF, AcOH (48% over 395, the hydroxy-directed hydrostannation was achieved 4 steps) MeO Me tBu by sequential desilylation and treatment with Bu3SnH, in Ar Ar MeO P AuCl Me the presence of catalytic amounts of [Cp*RuCl2]n, to obtain Ar = OMe MeO P AuCl N the corresponding stannane 426 as a single regio- and ste- Ar O Ar tBu O O reoisomer. The methylation was then achieved according to 436 OH previous conditions to provide the desired methyl deriva- Me O O tive in a reasonably good yield (70%). The methylation of P Me HO OH O the hydroxy group proved to be similarly challenging, finding, after extensive experimentation, that the methyl ester Enigmazole A (428) 427 provided a proper source of electrophilic methyl by its Me Me Me a) K CO , MeOH (80%) Me in situ generation in a gold-catalyzed cyclization. Final re- Me 2 3 Me b) TFA (76%) ductive cleavage of the phenacyl group furnished the tar- OR O c) Ac2O, pyr (97%) O O O O geted natural product 420 (Scheme 51). d) 437 (84%) O RCM O t Beyond the transformation of the alkyne into an alkene (91%) Bu SbF6 t Bu P Au NCMe Me or even a methyl-substituted alkene, as discussed vide su- Catalyst Me OAc pra, the reactivity of the alkyne functional group allows the 397 OTBS 433 (R = C(O)CHCl ) 440 construction of a heterocyclic ring, providing further ex- 2 437 traordinary opportunities to access more complex structur- Me Me Me al systems compared to the alkene chemistry. Me Me These post-metathetic transformations have been simi- HO O O O O 218 larly explored by the Fürstner group in the synthesis of a [Lee, 2010] O plethora of natural products. In this set of new synthetic Me opportunities, the syntheses of enigmazole A (428) O MeO O (Scheme 52),213 polycavernoside A (429) (Scheme 52),214 O Me O OMe 215 OMe kendomycin (430) (Scheme 53), and lytharanidine (431) OMe Polycavernoside A (429) (Scheme 53)216 represent excellent examples of this syn- OH Scheme 52 Selected natural products synthesized via a RCAM/gold thetic potential. In all these cases, the macrocyclic alkynes This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. catalysis by the Fürstner group 432–435 were efficiently synthesized from their corresponding acyclic dialkynes. From these alkynes, in the cases of enigmazole A, polycavernoside A, and kendomycin, a An intriguing last case is the synthesis of ivorenolide B transannular pyran (for enigmazole A) and a furan ring (for (443) by the Fürstner group based upon a macrocyclization polycavernoside A and kendomycin) were efficiently con- of a diterminal diyne to prepare the 1,3-diyne system found structed by means of activation of the alkyne with gold- in this unprecedented natural product (Scheme 54).220 Ivo- based catalysts 436–438217 to provide compounds 439– renolide B belongs to a family of macrolides isolated from 441. In the cases of polycavernoside A and kendomycin, the the stem bark of Khaya ivorensis, which has been reported syntheses were formal, having been described their total to inhibit concanavalin A induced T-cell and lipopolysac- synthesis by Lee and Woo218 and Mulzer and co-workers219 charide-induced B cell proliferations. This noteworthy bio- from advanced precursors 440 and 442, respectively. On the logical activity confers it a clinical application as an immu- other hand, for the synthesis of lytharanidine (431), forma- nosuppressive agent comparable to cyclosporine A. The tion of a piperidine ring was required, which was achieved synthesis by the Fürstner group was delineated according

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

olefin as the major isomer. Despite this stereochemical Me Me Catalyst Me Me 395 problem, this synthesis allowed the absolute configuration Me Me Me Me RCAM a) K2CO3, MeOH (86%) of the natural product to be confirmed (Scheme 54). (95%) b) 438 (79%) O O Me tBu Me O Me t Me O OAc Bu O 4.2 Other Types of Alkyne-Metathesis Reactions Me P Au OTs Me O O Me O O Me OMe To conclude this review, it is necessary to mention that, 434OMe 438 441 c) hv (85%) e) HCl as in alkene metathesis reactions, we can find also exam- d) NaBH4 (89% over ples of the use of the alkyne cross-metathesis222 or tethered 2 steps) 223 Me Me Me Me RCAM reactions. Despite the power and scope that the

Me Me Me Me alkyne metathesis demonstrates, utilization of these alkyne [Mulzer, 2010]219 metathesis variants in the context of total synthesis is not Me OH Me O O O O well represented, with most examples being found mainly HO HO in polymerization reactions.224 Nevertheless, given the po- Me Me Me Me HO HO tential and efficiency of the methodology, there is no doubt O OMe that the trend will be an increase in the use of this chemis- Kendomycin (430) 442 try in the construction of natural products. OMe OMe HO HO a) [IndRu(PPh3)2Cl] In(OTf)3, CSA (74%) b) TsOH, 45 ºC (67%) OTBDPS OH OH HO 5 Conclusions NHCbz t H c) LiAlH(O Bu)3, LiCl (92%) N d) H2, Pd (93%) e) TBAF, HOAc (82%) As amply demonstrated in the literature, metathesis re- RCAM Lythranidine (431) actions are recognized as one of the most important and Catalyst 435 397 powerful reactions in the last decades rendering their main inventors the Nobel Prize in 2005. The synthetic value and Scheme 53 Selected natural products synthesized via a RCAM/gold catalysis by the Fürstner group great potential of these reactions have been driven by the tremendous progress witnessed in recent years regarding the design and development of efficient and stable catalysts to a RCAM reaction of the diterminal acyclic diyne 444, based on metallocarbenes. As a consequence, these reac- which by treatment with catalyst 395 furnished in a re- tions enjoy broad scope and generality and a great deal of markable 82% yield the desired [17]-membered ring 445 flexibility for structural diversity. Furthermore, as proof of with the embedded 1,3-diyne unit and no detection of side these features is their extensive utilization in the field of or- products derived from ring contraction or oligomerization ganic synthesis, with particular impact in the total synthe- processes. The subsequent epoxidation, performed in a re- sis of natural products. These reactions in their different gio- and stereoselective manner with mCPBA, followed by modalities (alkene-, enyne-, and alkyne-metathesis reac- silyl ether deprotection provided the targeted ivorenolide B tions), versions (intra- and intermolecular reactions), and (443) (Scheme 54). This synthesis improved notably by Yue strategies (tethered, relay, stereoselective metathesis, and co-workers,221 who, based on a RCM reaction, provided among others) have become a standard tool in the modern the macrocyclic lactone 446 as a 1.5:1 mixture with the E- organic synthesis laboratory, being determinant in the completion of a wide array of natural products. In the pres- Me

ent review we have covered the most relevant contribu- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. tions on this field in the last five years, demonstrating the increasing value and flurry of synthetic opportunities that OTBS Me OTBS these reactions provide. Me a) 395, toluene O O (82%) O O 444 445 Funding Information b) m-CPBA (59% over c) TBAF 2 steps) This work was supported financially by the Ministerio de Economía y TBDPS Competitividad (MINECO) (Reference CTQ2014-60223-R)Mneistoir de Economaí y Compvditeiatd M(NIECO ) C(TQ2014-60223-R) Me O Me OH RCM a) mCPBA O b) TBAF O O 221 O [Yue, 2014] O Acknowledgment 446 (93%; E/Z = 1.5:1) Ivorenolide B (443) I. C.-S. thanks the Ministerio de Educación, Cultura y Deporte (FPU Scheme 54 Total synthesis of ivorenolide B Programme) for a predoctoral fellowship. The authors thank Dr. J. I.

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

Trujillo (Pfizer, Groton, CT) for assistance in the preparation of this (24) Kingsbury, J. S.; Garber, S. B.; Giftos, J. M.; Gray, B. L.; Okamoto, manuscript. M. M.; Farrer, R. A.; Fourkas, J. T.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2001, 40, 4251. (25) (a) Lin, Y. A.; Chalker, J. M.; Davis, B. G. ChemBioChem 2009, 10, References 959. (b) Burtscher, D.; Grela, K. Angew. Chem. Int. Ed. 2009, 48, 442. (1) Metathesis reactions include not only alkene, enyne, and alkyne (26) All these metal–carbene complexes are indeed precatalysts or metatheses, but also carbonyl–olefin metathesis, which are not initiators rather than catalysts because they are not recovered included in this review. For representative reviews about these unchanged at the end of the process. As the term ‘catalyst’ is reactions see: (a) Ravindar, L.; Lekkala, R.; Rakesh, K. P.; Asiri, A. generally accepted in the literature, we have opted to use this A.; Marwani, H. M.; Quin, H.-L. Org. Chem. Front. 2018, 5, 1381. term in this review. (b) Ludwig, J. R.; Schindler, C. S. Synlett 2017, 28, 1501. (27) For an excellent review about the evolution of catalyst design, (2) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Wein- see: Hoveyda, A. H. J. Org. Chem. 2014, 79, 4763. heim, 2015, 2nd ed., Vols. 1–3. (28) Selected reviews on applications of the metathesis reactions in (3) McGinnis, J.; Katz, T. J.; Hurwitz, S. J. Am. Chem. Soc. 1976, 98, total synthesis: (a) Ivin, K. J. J. Mol. Catal. A: Chem. 1998, 133, 1. 605. (b) Prunet, J. Angew. Chem. Int. Ed. 2003, 42, 2826. (c) Schrock, R. (4) Hérisson, J.-L.; Chauvin, Y. Makromol. Chem. 1971, 141, 161. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592. (5) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, (d) Mulzer, J.; Öhler, E. Top. Organomet. Chem. 2004, 13, 269. M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875. (e) Rouge dos Santos, A.; Kaiser, C. R. Quim. Nova 2008, 31, 655. (6) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, (f) Hoveyda, A. H.; Malcolmson, S. J.; Meek, S. J.; Zhugralin, A. R. 9856. Angew. Chem. Int. Ed. 2010, 49, 34. (g) Fürstner, A. Chem. (7) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Commun. 2011, 47, 6505. (h) Lei, X.; Li, H. Top. Curr. Chem. 2012, Chem., Int. Ed. Engl. 1995, 34, 2039. 327, 163. (i) Bose, S.; Ghosh, S. Proc. Indian Natl. Sci. Acad. 2014, (8) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 80, 37. 953. (29) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. (9) Harrity, J. P. A.; La, D. S.; Cefalo, D. R.; Visser, M. S.; Hoveyda, A. 2005, 44, 4490. H. J. Am. Chem. Soc. 1998, 120, 2343. (30) Gradillas, A.; Pérez-Castells, J. Angew. Chem. Int. Ed. 2006, 45, (10) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. 6086. Chem. Soc. 2000, 122, 8168. (31) Prunet, J. Eur. J. Org. Chem. 2011, 3634. (11) Wakamatsu, H.; Blechert, S. Angew. Chem. Int. Ed. 2002, 41, (32) Vanderwal, C. D.; Atwood, B. R. Aldrichimica Acta 2017, 50, 17. 2403. (33) Metathesis in Natural Product Synthesis; Cossy, J.; Arseniyadis, (12) Fürstner, A.; Grabowski, J.; Lehmann, C. W. J. Org. Chem. 1999, S.; Meyer, C., Eds.; Wiley-VCH: Weinheim, 2010. 64, 8275. (34) Selected reviews on metathesis reactions in synthesis of spe- (13) Jafarpour, L.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organome- cific types of natural products: (a) Mulzer, J.; Öhler, E.; Enev, V. tallics 1999, 18, 5416. S.; Hanbauer, M. Adv. Synth. Catal. 2002, 344, 573. (b) Felpin, F.- (14) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem. Int. Ed. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693. (c) Mutlak, H.; 2002, 41, 4038. Hassan, A. Chem. Commun. 2010, 46, 9100. (d) Morzycki, J. W. (15) Zhan, Z. J. US 20070043180, 2007; Chem. Abstr. 2007, 146, Steroids 2011, 76, 949. (e) Demonceau, A.; Dragutan, I.; 142834 Dragutan, V.; Le Gendre, P. Curr. Org. Synth. 2012, 9, 779. (16) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; (f) Bajwa, N.; Jennings, M. P. Strategies Tactics Org. Synth. 2012, Schrodi, Y. Org. Lett. 2007, 9, 1589. 8, 153. (g) Yu, X.; Sun, D. Molecules 2013, 18, 6230. (h) Nguyen, (17) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem. T. V.; Hartmann, J. M.; Enders, D. Synthesis 2013, 45, 845. Int. Ed. 2002, 41, 4035. (i) Lazarski, K. E.; Moritz, B. J.; Thomson, R. J. Angew. Chem. Int. (18) Williams, M. J.; Kong, J.; Chung, C. K.; Brunskill, A.; Campeau, L.- Ed. 2014, 53, 10588. (j) Wojtkielewicz, A. Curr. Org. Synth. 2013, C.; McLaughlin, M. Org. Lett. 2016, 18, 1952. 10, 43. (k) Fuwa, H.; Sasaki, M. Bull. Chem. Soc. Jpn. 2016, 89, (19) (a) Malcolmson, S. J.; Meek, S. J.; Sattely, E. S.; Schrock, R. R.; 1403. (l) Jacques, R.; Pal, R.; Parker, N. A.; Sear, C. E.; Smith, P. Hoveyda, A. H. Nature (London) 2008, 456, 933. (b) Lee, Y.-L.;

W.; Ribaucourt, A.; Hodgson, D. M. Org. Biomol. Chem. 2016, 14, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 10652. 5875. (c) Sattely, E. S.; Meek, S. J.; Malcolmson, S. J.; Schrock, R. R.; (35) (a) Glaus, F.; Altmann, K.-H. Angew. Chem. Int. Ed. 2012, 51, Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 943. (d) Yu, M.; 3405. (b) Winter, P.; Hiller, W.; Christmann, M. Angew. Chem. Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Int. Ed. 2012, 51, 3396. (c) Tang, W.; Prusov, E. V. Angew. Chem. Hoveyda, A. H. Nature (London) 2011, 479, 88. (e) Wang, C.; Int. Ed. 2012, 51, 3401. Haeffner, F.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. (36) Tang, W.; Prusov, E. V. Org. Lett. 2012, 14, 4690. 2013, 52, 1939. (37) Villa, R.; Mandel, A. L.; Jones, B. D.; La Clair, J. J.; Burkart, M. D. (20) Jiang, A. J.; Simpson, J. H.; Müller, P.; Schrock, R. R. J. Am. Chem. Org. Lett. 2012, 14, 5396. Soc. 2009, 131, 7770. (38) Kusuma, B. R.; Brandt, G. E. L.; Blagg, B. S. J. Org. Lett. 2012, 14, (21) (a) Rosebrugh, L. E.; Herbert, M. B.; Marx, V. M.; Keitz, B. K.; 6242. Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 1276. (b) Cannon, J. S.; (39) Oh, H.-S.; Kang, H.-Y. J. Org. Chem. 2012, 77, 1125. Grubbs, R. H. Angew. Chem. Int. Ed. 2013, 52, 9001. (40) Ghosh, A. K.; Cheng, X.; Bai, R.; Hamel, E. Eur. J. Org. Chem. 2012, (22) (a) Khan, R. K. M.; Torker, S.; Hoveyda, A. H. J. Am. Chem. Soc. 4130. 2013, 135, 10258. (b) Koh, M. J.; Khan, R. K. M.; Torker, S.; Yu, (41) Hara, A.; Morimoto, R.; Iwasaki, Y.; Saitoh, T.; Ishikawa, Y.; M.; Mikus, M. S.; Hoveyda, A. H. Nature (London) 2015, 517, 181. Nishiyama, S. Angew. Chem. Int. Ed. 2012, 51, 9877. (23) Hong, S. H.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 3508. (42) Pawar, A. B.; Prasad, K. R. Chem. Eur. J. 2012, 18, 15202.

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

(43) Becker, J.; Butt, L.; von Kiedrowski, V.; Mischler, E.; Quentin, F.; (74) Reddy, D. P.; Zhang, N.; Yu, Z.; Wang, Z.; He, Y. J. Org. Chem. Hiersemann, M. Org. Lett. 2013, 15, 5982. 2017, 82, 11262. (44) Fuwa, H.; Ishigai, K.; Hashizume, K.; Sasaki, M. J. Am. Chem. Soc. (75) Revu, O.; Prasad, K. R. J. Org. Chem. 2017, 82, 438. 2012, 134, 11984. (76) Toelle, N.; Weinstabl, H.; Gaich, T.; Mulzer, J. Angew. Chem. Int. (45) Kondoh, A.; Arlt, A.; Gabor, B.; Fürstner, A. Chem. Eur. J. 2013, 19, Ed. 2014, 53, 3859. 7731. (77) Zhu, L.; Liu, Y.; Ma, R.; Tong, R. Angew. Chem. Int. Ed. 2015, 54, (46) Del Valle, D. J.; Krische, M. J. J. Am. Chem. Soc. 2013, 135, 10986. 627. (47) Fuwa, H.; Yamagata, N.; Saito, A.; Sasaki, M. Org. Lett. 2013, 15, (78) Frichert, A.; Jones, P. G.; Lindel, T. Angew. Chem. Int. Ed. 2016, 55, 1630. 2916. (48) Takada, A.; Uda, K.; Ohtani, T.; Tsukamoto, S.; Takahashi, D.; (79) Zhang, P.-P.; Yan, Z.-M.; Li, Y.-H.; Gong, J.-X.; Yang, Z. J. Am. Toshima, K. J. Antibiot. 2013, 66, 155. Chem. Soc. 2017, 139, 13989. (49) Terayama, N.; Yasui, E.; Mizukami, M.; Miyashita, M.; Nagumo, (80) Matsuzawa, A.; Shiraiwa, J.; Kasamatsu, A.; Sugita, K. Org. Lett. S. Org. Lett. 2014, 16, 2794. 2018, 20, 1031. (50) Saidhareddy, P.; Ajay, S.; Shaw, A. K. RSC Adv. 2014, 4, 4253. (81) (a) Wadsworth, A. D.; Furkert, D. P.; Sperry, J.; Brimble, M. A. (51) Kanoh, N.; Kawamata, A.; Itagaki, T.; Miyazaki, Y.; Yahata, K.; Org. Lett. 2012, 14, 5374. (b) Wadsworth, A. D.; Furkert, D. P.; Kwon, E.; Iwabuchi, Y. Org. Lett. 2014, 16, 5216. Brimble, M. A. J. Org. Chem. 2014, 79, 11179. (52) (a) Hallside, M. S.; Brzozowski, R. S.; Wuest, W. M.; Phillips, A. J. (82) Schafroth, M. A.; Zuccarello, G.; Krautwald, S.; Sarlah, D.; Org. Lett. 2014, 16, 1148. (b) Kuilya, T. K.; Goswami, R. K. Org. Carreira, E. M. Angew. Chem. Int. Ed. 2014, 53, 13898. Lett. 2017, 19, 2366. (83) (a) Trost, B. M.; Dogra, K. Org. Lett. 2007, 9, 861. (b) Song, Y.; (53) Chatterjee, S.; Guchhait, S.; Goswami, R. K. J. Org. Chem. 2014, Hwang, S.; Gong, P.; Kim, D.; Kim, S. Org. Lett. 2008, 10, 269. 79, 7689. (84) Yang, J.; Knueppel, D.; Cheng, B.; Mans, D.; Martin, S. F. Org. Lett. (54) Fujiwara, K.; Suzuki, Y.; Koseki, N.; Aki, Y.-i.; Kikuchi, Y.; Murata, 2015, 17, 114. S.-i.; Yamamoto, F.; Kawamura, M.; Norikura, T.; Matsue, H.; (85) Chapman, L. M.; Beck, J. C.; Wu, L.; Reisman, S. E. J. Am. Chem. Murai, A.; Katoono, R.; Kawai, H.; Suzuki, T. Angew. Chem. Int. Soc. 2016, 138, 9803. Ed. 2014, 53, 780. (86) Takamura, H.; Kikuchi, T.; Endo, N.; Fukuda, Y.; Kadota, I. Org. (55) (a) Bali, A. K.; Sunnam, S. K.; Prasad, K. R. Org. Lett. 2014, 16, Lett. 2016, 18, 2110. 4001. (b) Sharma, B. M.; Gontala, A.; Kumar, P. Eur. J. Org. Chem. (87) Chuang, K. V.; Xu, C.; Reisman, S. E. Science (Washington, D. C.) 2016, 1215. 2016, 353, 912. (56) Pradhan, T. R.; Das, P. P.; Mohapatra, D. K. Synthesis 2014, 46, (88) (a) Nagatomo, M.; Koshimizu, M.; Masuda, K.; Tabuchi, T.; 1177. Urabe, D.; Inoue, M. J. Am. Chem. Soc. 2014, 136, 5916. (57) Kumar, S. M.; Prasad, K. R. Chem. Asian J. 2014, 9, 3431. (b) Koshimizu, M.; Nagatomo, M.; Inoue, M. Angew. Chem. Int. (58) Ohba, K.; Nakata, M. Org. Lett. 2015, 17, 2890. Ed. 2016, 55, 2493. (c) Masuda, K.; Koshimizu, M.; Nagatomo, (59) (a) Kaufmann, E.; Hattori, H.; Miyatake-Ondozabal, H.; M.; Inoue, M. Chem. Eur. J. 2016, 22, 230. Gademann, K. Org. Lett. 2015, 17, 3514. (b) Miyatake-Ondoza- (89) For reviews on catalytic enantioselective olefin metathesis, see: bal, H.; Kaufmann, E.; Gademann, K. Angew. Chem. Int. Ed. 2015, (a) ref. 27. (b) Montgomery, T. P.; Johns, A. M.; Grubbs, R. H. Cat- 54, 1933. alysts 2017, 7, 87. (60) (a) Li, H.; Xie, H.; Zhang, Z.; Xu, Y.; Lu, J.; Gao, L.; Song, Z. Chem. (90) Kang, T.; White, K. L.; Mann, T. J.; Hoveyda, A. H.; Movassaghi, Commun. 2015, 51, 8484. (b) Zhang, Z.; Xie, H.; Li, H.; Gao, L.; M. Angew. Chem. Int. Ed. 2017, 56, 13857. Song, Z. Org. Lett. 2015, 17, 4706. (91) Cheng, B.; Sunderhaus, J. D.; Martin, S. F. Tetrahedron 2015, 71, (61) Yu, M.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2015, 7323. 54, 215. (92) Vincent, G.; Mansfield, D. J.; Vors, J.-P.; Ciufolini, M. A. Org. Lett. (62) Suzuki, T.; Fujimura, M.; Fujita, K.; Kobayashi, S. Tetrahedron 2006, 8, 2791. 2017, 73, 3652. (93) Lu, H.-H.; Hinkelmann, B.; Tautz, T.; Li, J.; Sasse, F.; Franke, R.; (63) Sakamoto, K.; Hakamata, A.; Tsuda, M.; Fuwa, H. Angew. Chem. Kalesse, M. Org. Biomol. Chem. 2015, 13, 8029. Int. Ed. 2018, 57, 3801. (94) Canterbury, D. P.; Scott, K. E. N.; Kubo, O.; Jansen, R.; Cleveland, (64) Jakubec, P.; Hawkins, A.; Felzmann, W.; Dixon, D. J. J. Am. Chem. J. L.; Micalizio, G. C. ACS Med. Chem. Lett. 2013, 4, 1244.

Soc. 2012, 134, 17482. (95) Trost, B. M.; Yang, H.; Dong, G. Chem. Eur. J. 2011, 17, 9789. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (65) Miura, Y.; Hayashi, N.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. (96) Dumeunier, R.; Gregson, T.; MacCormick, S.; Omori, H.; Thomas, Soc. 2012, 134, 11995. E. J. Org. Biomol. Chem. 2017, 15, 2768. (66) Chausset-Boissaire, L.; Árvai, R.; Cumming, G. R.; Guénée, L.; (97) Kim, B.; Sohn, T.-i.; Kim, D.; Paton, R. S. Chem. Eur. J. 2018, 24, Kündig, E. P. Org. Biomol. Chem. 2012, 10, 6473. 2634. (67) Pfeiffer, B.; Speck-Gisler, S.; Barandun, L.; Senft, U.; de Groot, C.; (98) Fujiwara, K. Top. Heterocycl. Chem. 2006, 5, 97. Lehmann, I.; Ganci, W.; Gertsch, J.; Altmann, K.-H. J. Org. Chem. (99) Hansen, E. C.; Lee, D. Org. Lett. 2004, 6, 2035. 2013, 78, 2553. (100) Monfette, S.; Eyholzer, M.; Roberge, D. M.; Fogg, D. E. Chem. Eur. (68) Mahipal, B.; Singh, A.; Ummanni, R.; Chandrasekhar, S. RSC Adv. J. 2010, 16, 11720. 2013, 3, 15917. (101) Skowerski, K.; Czarnocki, S. J.; Knapkiewicz, P. ChemSusChem (69) Toya, H.; Satoh, T.; Okano, K.; Takasu, K.; Ihara, M.; Takahashi, 2014, 7, 536. A.; Tanaka, H.; Tokuyama, H. Tetrahedron 2014, 70, 8129. (102) Morin, E.; Raymond, M.; Dubart, A.; Collins, S. K. Org. Lett. 2017, (70) Rensing, D. T.; Uppal, S.; Blumer, K. J.; Moeller, K. D. Org. Lett. 19, 2889. 2015, 17, 2270. (103) Chen, R.; Li, L.; Lin, N.; Zhou, R.; Hua, Y.; Deng, H.; Zhang, Y. Org. (71) Huang, J.; Wang, Z. Org. Lett. 2016, 18, 4702. Lett. 2018, 20, 1477. (72) Clark, J. S.; Xu, C. Angew. Chem. Int. Ed. 2016, 55, 4332. (104) Weiß, C.; Bogner, T.; Sammet, B.; Sewald, N. Beilstein J. Org. (73) Xu, B.; Li, G.; Li, J.; Shi, Y. Org. Lett. 2016, 18, 2028. Chem. 2012, 8, 2060.

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

(105) Yadav, J. S.; Das, S. K.; Sabitha, G. J. Org. Chem. 2012, 77, 11109. (138) Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H. R. (106) Persich, P.; Kerschbaumer, J.; Helling, S.; Hildmann, B.; J. Am. Chem. Soc. 2003, 125, 14702. Wibbeling, B.; Haufe, G. Org. Lett. 2012, 14, 5628. (139) Chowdhury, P. S.; Kumar, P. Eur. J. Org. Chem. 2013, 4586. (107) Reddy, C. R.; Jithender, E.; Prasad, K. R. J. Org. Chem. 2013, 78, (140) Kumar, T. V.; Shankaraiah, G.; Babu, K. S.; Rao, J. M. Tetrahedron 4251. Lett. 2013, 54, 1397. (108) Yajima, A.; Kawajiri, A.; Mori, A.; Katsuta, R.; Nukada, T. Tetrahe- (141) Kumar, T. V.; Reddy, G. V.; Babu, K. S.; Rao, J. M. Tetrahedron: dron Lett. 2014, 55, 4350. Asymmetry 2013, 24, 594. (109) Konda, S.; Bhaskar, K.; Nagarapu, L.; Akkewar, D. M. Tetrahedron (142) Volchkov, I.; Lee, D. J. Am. Chem. Soc. 2013, 135, 5324. Lett. 2014, 55, 3087. (143) (a) Jung, J.-C.; Kache, R.; Vines, K. K.; Zheng, Y.-S.; Bijoy, P.; (110) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Stonehouse, J. P.; Valluri, M.; Avery, M. A. J. Org. Chem. 2004, 69, 9269. (b) Prantz, Thomson, J. E. J. Org. Chem. 2012, 77, 7028. K.; Mulzer, J. Angew. Chem. Int. Ed. 2009, 48, 5030. (111) Dayaker, G.; Krishna, P. R. Helv. Chim. Acta 2014, 97, 868. (144) Gaich, T.; Mulzer, J. Org. Lett. 2005, 7, 1311. (112) Gao, Y.; Shan, Q.; Liu, J.; Wang, L.; Du, Y. Org. Biomol. Chem. (145) Wang, J.; Sun, B.-F.; Cui, K.; Lin, G.-Q. Org. Lett. 2012, 14, 6354. 2014, 12, 2071. (146) Clark, J. S.; Romiti, F. Angew. Chem. Int. Ed. 2013, 52, 10072. (113) Kamal, A.; Balakrishna, M.; Reddy, P. V.; Rahim, A. Tetrahedron: (147) Schmidt, B.; Audörsch, S. J. Org. Chem. 2017, 82, 1743. Asymmetry 2014, 25, 148. (148) Liu, C.-W.; Yeh, T.-C.; Chen, C.-H.; Yu, C.-C.; Chen, C.-S.; Hou, D.- (114) Suzuki, A.; Sasaki, M.; Nakagishi, T.; Ueda, T.; Hoshiya, N.; R.; Guh, J.-H. Tetrahedron 2013, 69, 2971. Uenishi, J. Org. Lett. 2016, 18, 2248. (149) Jayasinghe, S.; Venukadasula, P. K. M.; Hanson, P. R. Org. Lett. (115) Srinivas, E.; Dutta, P.; Ganganna, B.; Alghamdi, A. A.; Yadav, J. S. 2014, 16, 122. Synthesis 2016, 48, 1561. (150) Bodugam, M.; Javed, S.; Ganguly, A.; Torres, J.; Hanson, P. R. Org. (116) von Kiedrowski, V.; Quentin, F.; Hiersemann, M. Org. Lett. 2017, Lett. 2016, 18, 516. 19, 4391. (151) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. (117) Reddy, G. S.; Padhi, B.; Bharath, Y.; Mohapatra, D. K. Org. Lett. J. Am. Chem. Soc. 2004, 126, 10210. 2017, 19, 6506. (152) Wang, X.; Bowman, E. J.; Bowman, B. J.; Porco, J. A. Jr. Angew. (118) Cheng, H.; Zhang, Z.; Yao, H.; Zhang, W.; Yu, J.; Tong, R. Angew. Chem. Int. Ed. 2004, 43, 3601. Chem. Int. Ed. 2017, 56, 9096. (153) For a review on RRCM, see: Wallace, D. J. Angew. Chem. Int. Ed. (119) Gregg, C.; Gunawan, C.; Ng, A. W. Y.; Wimala, S.; 2005, 44, 1912. Wickremasinghe, S.; Rizzacasa, M. A. Org. Lett. 2013, 15, 516. (154) Fujioka, K.; Yokoe, H.; Yoshida, M.; Shishido, K. Org. Lett. 2012, (120) Paterson, I.; Findlay, A. D.; Noti, C. Chem. Asian J. 2009, 4, 594. 14, 244. (121) Kumar, D. A.; Meshram, H. M. Synth. Commun. 2013, 43, 1145. (155) Arndt, H.-D.; Rizzo, S.; Nöcker, C.; Wakchaure, V. N.; Milroy, L.- (122) Ghosh, A. K.; Veitschegger, A. M.; Sheri, V. R.; Effenberger, K. A.; G.; Bieker, V.; Calderon, A.; Tran, T. T. N.; Brand, S.; Dehmelt, L.; Prichard, B. E.; Jurica, M. S. Org. Lett. 2014, 16, 6200. Waldmann, H. Chem. Eur. J. 2015, 21, 5311. (123) (a) Ghosh, A. K.; Chen, Z.-H. Org. Lett. 2013, 15, 5088. (b) Ghosh, (156) Wang, C.; Yu, M.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. A. K.; Chen, Z.-H.; Effenberger, K. A.; Jurica, M. S. J. Org. Chem. R.; Hoveyda, A. H. Chem.–Eur. J. 2013, 19, 2726. 2014, 79, 5697. (157) Herbert, M. B.; Suslick, B. A.; Liu, P.; Zou, L.; Dornan, P. K.; Houk, (124) Kita, M.; Oka, H.; Usui, A.; Ishitsuka, T.; Mogi, Y.; Watanabe, H.; K. N.; Grubbs, R. H. Organometallics 2015, 34, 2858. Tsunoda, M.; Kigoshi, H. Angew. Chem. Int. Ed. 2015, 54, 14174. (158) (a) Johns, A. M.; Ahmed, T. S.; Jackson, B. W.; Grubbs, R. H.; (125) Glaus, F.; Altmann, K.-H. Angew. Chem. Int. Ed. 2015, 54, 1937. Pederson, R. L. Org. Lett. 2016, 18, 772. (b) Ahmed, T. S.; Grubbs, (126) Erb, W.; Grassot, J.-M.; Linder, D.; Neuville, L.; Zhu, J. Angew. R. H. J. Am. Chem. Soc. 2017, 139, 1532. Chem. Int. Ed. 2015, 54, 1929. (159) (a) Montgomery, T. P.; Ahmed, T. S.; Grubbs, R. H. Angew. Chem. (127) Jeanne-Julien, L.; Masson, G.; Astier, E.; Genta-Jouve, G.; Int. Ed. 2017, 56, 11024. (b) Montgomery, T. P.; Grandner, J. M.; Servajean, V.; Beau, J.-M.; Norsikian, S.; Roulland, E. Org. Lett. Houk, K. N.; Grubbs, R. H. Organometallics 2015, 36, 3940. 2017, 19, 4006. (160) Hartung, J.; Dornan, P. K.; Grubbs, R. H. J. Am. Chem. Soc. 2014, (128) (a) Takahashi, S.; Satoh, D.; Hayashi, M.; Takahashi, K.; 136, 13029. Yamaguchi, K.; Nakamura, T.; Koshino, H. J. Org. Chem. 2016, 81, (161) (a) Herbert, M. B.; Grubbs, R. H. Angew. Chem. Int. Ed. 2015, 54, 11222. (b) Takahashi, S.; Hongo, Y.; Tsukagoshi, Y.; Koshino, H. 5018. (b) Werrel, S.; Walker, J. C. L.; Donohoe, T. J. Tetrahedron

Org. Lett. 2008, 10, 4223. Lett. 2015, 56, 5261. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (129) Alfonso, D.; Colman-Saizarbitoria, T.; Zhao, G.-X.; Shi, G.; Ye, Q.; (162) Mangold, S. L.; Grubbs, R. H. Chem. Sci. 2015, 6, 4561. Schwedler, J. T.; McLaughlin, J. L. Tetrahedron 1996, 52, 4215. (163) (a) Mangold, S. L.; O’Leary, D. J.; Grubbs, R. H. J. Am. Chem. Soc. (130) Cheng-Sánchez, I.; García-Ruiz, C.; Guerrero-Vásquez, G. A.; 2014, 136, 12469. (b) Dornan, P. K.; Wickens, Z. K.; Grubbs, R. H. Sarabia, F. J. Org. Chem. 2017, 82, 4744. Angew. Chem. Int. Ed. 2015, 54, 7134. (c) Luo, S.-X.; Cannon, J. S.; (131) Shimada, J.; Kwon, H. J.; Sawamura, M.; Schreiber, S. L. Chem. Taylor, B. L. H.; Engle, K. M.; Houk, K. N.; Grubbs, R. H. J. Am. Biol. 1995, 2, 517. Chem. Soc. 2016, 138, 14039. (d) Dornan, P. K.; Lee, D.; Grubbs, (132) García-Ruiz, C.; Cheng-Sánchez, I.; Sarabia, F. Org. Lett. 2015, 17, R. H. J. Am. Chem. Soc. 2016, 138, 6372. (e) de Léséleuc, M.; 5558. Godin, E.; Parisien-Collette, S.; Lévesque, A.; Collins, S. K. J. Org. (133) Bisterfeld, C.; Holec, C.; Böse, D.; Marx, P.; Pietruszka, J. J. Nat. Chem. 2016, 81, 6750. (f) Xu, C.; Shen, X.; Hoveyda, A. H. J. Am. Prod. 2017, 80, 1563. Chem. Soc. 2017, 139, 10919. (134) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426. (164) Speed, A. W. H.; Mann, T. J.; O’Brien, R. V.; Schrock, R. R.; (135) Cusak, A. Chem. Eur. J. 2012, 18, 5800. Hoveyda, A. H. J. Am. Chem. Soc. 2014, 136, 16136. (136) Matsui, R.; Seto, K.; Fujita, K.; Suzuki, T.; Nakazaki, A.; (165) For a recent review about the use of metathesis cascade reac- Kobayashi, S. Angew. Chem. Int. Ed. 2010, 49, 10068. tions in synthesis of natural products, see: Han, J.-C.; Li, C.-C. (137) Hoye, T. R.; Jeon, J.; Kopel, L. C.; Ryba, T. D.; Tennakoon, M. A.; Synlett 2015, 26, 1289. Wang, Y. Angew. Chem. Int. Ed. 2010, 49, 6151.

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

(166) Lee, H.-Y.; Lee, S.-S.; Kim, H. S.; Lee, K. M. Eur. J. Org. Chem. 2012, (194) Schrock, R. R.; Clark, D. N.; Sancho, J.; Wengrovius, J. H.; 4192. Rocklage, S. M.; Pedersen, S. F. Organometallics 1982, 1, 1645. (167) Shoji, M.; Akiyama, N.; Tsubone, K.; Lash, L. L.; Sanders, J. M.; (195) Fürstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 1999, Swanson, G. T.; Sakai, R.; Shimamoto, K.; Oikawa, M.; Sasaki, M. 121, 9453. J. Org. Chem. 2006, 71, 4227. (196) Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. (168) Horeischi, F.; Guttroff, C.; Plietker, B. Chem. Commun. 2015, 51, 1999, 121, 11108. 2259. (197) (a) Schaubach, S.; Gebauer, K.; Ungeheuer, F.; Hoffmeister, L.; (169) Horeischi, F.; Biber, N.; Plietker, B. J. Am. Chem. Soc. 2014, 136, Ilg, M. K.; Wirtz, C.; Fürstner, A. Chem. Eur. J. 2016, 22, 8494; and 4026. references therein. (b) Wu, X.; Tamm, M. Beilstein J. Org. Chem. (170) Takao, K.-i.; Nanamiya, R.; Fukushima, Y.; Namba, A.; Yoshida, 2011, 7, 82. K.; Tadano, K.-i. Org. Lett. 2013, 15, 5582. (198) Fürstner, A.; Mathes, C.; Lehmann, C. W. Chem. Eur. J. 2001, 7, (171) (a) Takao, K.-i.; Nemoto, R.; Mori, K.; Namba, A.; Yoshida, K.; 5299. Ogura, A. Chem. Eur. J. 2017, 23, 3828. (b) Takao, K.-i.; Mori, K.; (199) Selected reviews on alkyne metathesis: (a) Fürstner, A. Angew. Kasuga, K.; Nanamiya, R.; Namba, A.; Fukushima, Y.; Nemoto, Chem. Int. Ed. 2014, 53, 8587. (b) Fürstner, A. Angew. Chem. Int. R.; Mogi, T.; Yasui, H.; Ogura, A.; Yoshida, K.; Tadano, K.-i. J. Org. Ed. 2013, 52, 2794. (c) Zhang, W.; Moore, J. S. Adv. Synth. Catal. Chem. 2018, 83, 7060. 2007, 349, 93. (d) Fürstner, A.; Davies, P. W. Chem. Commun. (172) Waldeck, A. R.; Krische, M. J. Angew. Chem. Int. Ed. 2013, 52, 2005, 2307. 4470. (200) Micoine, K.; Persich, P.; Llaveria, J.; Lam, M.-H.; Maderna, A.; (173) Kammari, B. R.; Bejjanki, N. K.; Kommu, N. Tetrahedron: Asym- Loganzo, F.; Fürstner, A. Chem. Eur. J. 2013, 19, 7370. metry 2015, 26, 296. (201) (a) Willwacher, J.; Fürstner, A. Angew. Chem. Int. Ed. 2014, 53, (174) Calder, E. D. D.; McGonagle, F. I.; Harkiss, A. H.; McGonagle, G. 4217. (b) Willwacher, J.; Heggen, B.; Wirtz, C.; Thiel, W.; A.; Sutherland, A. J. Org. Chem. 2014, 79, 7633. Fürstner, A. Chem. Eur. J. 2015, 21, 10416. (175) Grafton, M. W.; Farrugia, L. J.; Sutherland, A. J. Org. Chem. 2013, (202) (a) Valot, G.; Regens, C. S.; O’Malley, D. P.; Godineau, E.; 78, 7199. Takikawa, H.; Fürstner, A. Angew. Chem. Int. Ed. 2013, 52, 9534. (176) Selected reviews of enyne metathesis in synthesis of natural (b) Valot, G.; Mailhol, D.; Regens, C. S.; O’Malley, D. P.; products: (a) Mori, M. Materials 2010, 3, 2087. (b) Mori, M. Adv. Godineau, E.; Takikawa, H.; Phillipps, P.; Fürstner, A. Chem. Eur. Synth. Catal. 2007, 349, 121. (c) Dragutan, I.; Dragutan, V.; J. 2015, 21, 2398. Demonceau, A.; Delaude, L. Curr. Org. Chem. 2013, 17, 2678. (203) Fuchs, M.; Fürstner, A. Angew. Chem. Int. Ed. 2015, 54, 3978. (177) A general review about enyne metathesis: Diver, S. T.; Giessert, (204) Mailhol, D.; Willwacher, J.; Kausch-Busies, N.; Rubitski, E. E.; A. J. Chem. Rev. 2004, 104, 1317. Sobol, Z.; Schuler, M.; Lam, M.-H.; Musto, S.; Loganzo, F.; (178) Gao, X.; Woo, S. W.; Krische, M. J. J. Am. Chem. Soc. 2013, 135, Maderna, A.; Fürstner, A. J. Am. Chem. Soc. 2014, 136, 15719. 4223. (205) Lehr, K.; Schulthoff, S.; Ueda, Y.; Mariz, R.; Leseurre, L.; Gabor, (179) Jecs, E.; Diver, S. T. Org. Lett. 2015, 17, 3510. B.; Fürstner, A. Chem. Eur. J. 2015, 21, 219. (180) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945. (206) Hoffmeister, L.; Fukuda, T.; Pototschnig, G.; Fürstner, A. Chem. (181) Hwang, M.-h.; Han, S.-J.; Lee, D.-H. Org. Lett. 2013, 15, 3318. Eur. J. 2015, 21, 4529. (182) (a) Li, J.; Lee, D. Eur. J. Org. Chem. 2011, 4269. (b) Kotha, S.; (207) Neuhaus, C. M.; Liniger, M.; Stieger, M.; Altmann, K.-H. Angew. Meshram, M.; Tiwari, A. Chem. Soc. Rev. 2009, 38, 2065. Chem. Int. Ed. 2013, 52, 5866. (c) Kaliappan, K. P. Lett. Org. Chem. 2005, 2, 678. (208) Fouché, M.; Rooney, L.; Barrett, A. G. M. J. Org. Chem. 2012, 77, (183) Lee, J.; Parker, K. A. Org. Lett. 2012, 14, 2682. 3060. (184) Molawi, K.; Delpont, N.; Echavarren, A. M. Angew. Chem. Int. Ed. (209) Guo, L.-D.; Huang, X.-Z.; Luo, S.-P.; Cao, W.-S.; Ruan, Y.-P.; Ye, J.- 2010, 49, 3517. L.; Huang, P.-Q. Angew. Chem. Int. Ed. 2016, 55, 4064. (185) (a) Paquette, L. A.; Sauer, D. R.; Cleary, D. G.; Kinsella, M. A.; (210) Rummelt, S. M.; Preindl, J.; Sommer, H.; Fürstner, A. Angew. Blackwell, C. M.; Anderson, L. G. J. Am. Chem. Soc. 1992, 114, Chem. Int. Ed. 2015, 54, 6241. 7375. (b) Caussanel, F.; Wang, K.; Ramachandran, S. A.; (211) Kwon, Y.; Schulthoff, S.; Dao, Q. M.; Wirtz, C.; Fürstner, A. Chem. Deslongchamps, P. J. Org. Chem. 2006, 71, 7370. Eur. J. 2018, 24, 109. (186) Wang, Y.; Jäger, A.; Gruner, M.; Lübken, T.; Metz, P. Angew. (212) Meng, Z.; Souillart, L.; Monks, B.; Huwyler, N.; Herrmann, J.;

Chem. Int. Ed. 2017, 56, 15861. Müller, R.; Fürstner, A. J. Org. Chem. 2018, 83, in press; DOI: This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (187) Chu, S.; Münster, N.; Balan, T.; Smith, M. D. Angew. Chem. Int. Ed. 10.1021/acs.joc.7b02871. 2016, 55, 14306. (213) Ahlers, A.; de Haro, T.; Gabor, B.; Fürstner, A. Angew. Chem. Int. (188) Kress, S.; Weckesser, J.; Schulz, S. R.; Blechert, S. Eur. J. Org. Ed. 2016, 55, 1406. Chem. 2013, 1346. (214) Brewitz, L.; Llaveria, J.; Yada, A.; Fürstner, A. Chem. Eur. J. 2013, (189) Wei, H.; Qiao, C.; Liu, G.; Yang, Z.; Li, C.-c. Angew. Chem. Int. Ed. 19, 4532. 2013, 52, 620. (215) Hoffmeister, L.; Persich, P.; Fürstner, A. Chem. Eur. J. 2014, 20, (190) Honda, T.; Namiki, H.; Kaneda, K.; Mizutani, H. Org. Lett. 2004, 6, 4396. 87. (216) Gebauer, K.; Fürstner, A. Angew. Chem. Int. Ed. 2014, 53, 6393. (191) Magnus, P.; Rodríguez-López, J.; Mulholland, K.; Matthews, I. (217) Fürstner, A. Acc. Chem. Res. 2014, 47, 925. Tetrahedron 1993, 49, 8059. (218) Woo, S. K.; Lee, A. J. Am. Chem. Soc. 2010, 132, 4564. (192) Kashinath, K.; Jadhav, P. D.; Reddy, D. S. Org. Biomol. Chem. (219) Magauer, T.; Martin, H. J.; Mulzer, J. Chem. Eur. J. 2010, 16, 507. 2014, 12, 4098. (220) Ungeheuer, F.; Fürstner, A. Chem. Eur. J. 2015, 21, 11387. (193) Mortreux, A.; Blanchard, M. J. Chem. Soc., Chem. Commun. 1974, (221) Wang, Y.; Liu, Q.-F.; Xue, J.-J.; Zhou, Y.; Yu, H.-C.; Yang, S.-P.; 786. Zhang, B.; Zuo, J.-P.; Li, Y.; Yue, J.-M. Org. Lett. 2014, 16, 2062.

Syn thesis I. Cheng-Sánchez, F. Sarabia Review

(222) For a recent representative example see: Ralston, K. J.; (223) For a recent representative example see: Guy, A.; Oger, C.; Ramstadius, H. C.; Brewster, R. C.; Niblock, H. S.; Hulme, A. S. Heppekausen, J.; Signorini, C.; De Felice, C.; Fürstner, A.; Angew. Chem. Int. Ed. 2015, 54, 7086. Durand, T.; Galano, J.-M. Chem. Eur. J. 2014, 20, 6374. (224) Zhang, W.; Moore, J. S. Macromolecules 2004, 37, 3973; and references therein. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.