Design of Molecular Diversity by Olefin Metathesis in Tandem with Other Reactions

Sambasivarao Kotha; Naveen Kumar Gupta; Saima Ansari; Deepshikha Singh

doi:10.1055/a-2379-9912

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Synlett 2024; 35(20): 2297-2330
DOI: 10.1055/a-2379-9912

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Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu

Design of Molecular Diversity by Olefin Metathesis in Tandem with Other Reactions

Sambasivarao Kotha

^aDepartment of Chemistry, Sunandan Divaita School of Science, (SVKM’S NMIMS) (Deemed-to-be) University, Vile-Parle, Mumbai, Maharashtra, 400056, India

,

Naveen Kumar Gupta‡

^bDepartment of Chemistry, Indian Institute of Technology Bombay, Powai, Maharashtra, 400076, India

,

Saima Ansari‡

^bDepartment of Chemistry, Indian Institute of Technology Bombay, Powai, Maharashtra, 400076, India

,

Deepshikha Singh

^bDepartment of Chemistry, Indian Institute of Technology Bombay, Powai, Maharashtra, 400076, India

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Abstract

This review summarizes various strategies that combine metathesis with diverse named and unnamed reactions to create molecular diversity in producing carbocycles, macrocycles, and heterocycles.

1 Introduction

2 Olefinations

3 Rearrangement

4 Allylation

5 Cycloadditions

6 Coupling Reactions

7 Grignard Reaction

8 Radical reactions

9 Conjugate Addition–Metathesis

10 Multicomponent Reactions

11 Miscellaneous

12 Conclusions

#

Key words

metathesis - molecular diversity - carbocycles - macrocycles - heterocyclic compounds

Biographical Sketches

Sambasivarao Kotha graduated with an M.Sc. degree in Chemistry from the University of Hyderabad and obtained Ph.D. in Organic Chemistry from the University of Hyderabad in 1985. He continued his research at the University of Hyderabad as a postdoctoral fellow for one and a half years. Later, he moved to UMIST Manchester, UK, and the University of Wisconsin, USA as a research associate. Subsequently, he was appointed as a visiting scientist at Cornell University and as a research chemist at Hoechst Celanese Texas before joining IIT Bombay in 1994 as an assistant professor. Later, in 2001, he was promoted to Professor and superannuated during 2023. He is presently working as an adjunct professor at Department of Chemistry, Sunandan Divatia School of Science, Narsee Monjee Institute of Management Studies (NMIMS), Mumbai, India. He has published 375 publications in peer-reviewed journals and was elected a fellow of the various academies (FNASc, FASc, FRSC, and FNA). He was also associated with an editorial advisory board of several journals. His research interests include Organic synthesis, the development of new synthetic methods, unusual amino acids, cross-coupling reactions, metathesis, and theoretically interesting molecules.

Saima Ansari graduated with BSc (Hons.) in Chemistry in 2014 from Delhi University. In 2016, she received her MSc in Chemistry from IIT Hyderabad. She studied diazo-compounds computationally for her master's thesis. She worked under Professor Sambasivarao Kotha on the synthesis of propellanes and polyquinanes for her PhD at IIT Bombay in 2022, and she also spent a year as a postdoc there. She started working as a research fellow in Dr. Peter Knipe's group at Queen's University Belfast in 2023. Her current work focuses on foldamers and liquidcrystal mesogens.

Naveen Kumar Gupta received his B.Sc. degree in biotechnology in 2011 from the Govt. Model Science College, Jabalpur (affiliated with Rani Durgavati University Jabalpur, Madhya Pradesh). He subsequently joined the Department of Chemistry, University of Delhi, Delhi for his M.Sc. degree (organic chemistry) in 2012. In July 2016, he started his Ph.D. program at the Indian Institute of Technology (IIT) Bombay, Mumbai, as a CSIR-Junior Research Fellow in the Department of Chemistry under Prof. Sambasivarao Kotha. His doctorate was completed in November 2021. Following this, he worked as a research associate in Prof. Kotha's Group until December 2021, at which point he joined the Department of Chemistry at IIT Bombay, India, as an Institute Post-Doctoral Fellow (IPDF) (January 2022–January 2023). Subsequently, he moved to Washington, DC, USA, where he worked with Prof. Amol Kulkarni as a Postdoctoral Fellow at “Howard University, Washington, D.C., USA” (February 2023 to January 2024). As of February 2024, he relocated from Washington, D.C. to Texas along with Professor Amol Kulkarni and currently working as a postdoctoral fellow at The University of Texas at El Paso, Texas, USA.

Deepshikha Singh obtained her Bachelor of Science and Master of Science degrees in chemistry from HNB Garhwal University, Uttarakhand. During her master's program, she focused on the study of nanoparticles and served as a project assistant under the supervision of Professor Tanveer Alam, the Head of the Chemistry Department, for a duration of one year. In 2019, she commenced her Ph.D. studies at the Indian Institute of Technology (IIT) Bombay, Mumbai, in the Department of Chemistry, working under the guidance of Professor Sambasivarao Kotha on the synthesis of Pyrrole. She successfully completed her doctorate in 2024 and currently, engaged in postdoctoral research at IIT Bombay.

1

Introduction

Applications of olefin metathesis in combination with various named and unnamed reactions are compiled here. This review summarizes useful synthetic routes involving metathesis in combination with other reactions to generate intricate targets that are impossible or difficult to assemble by conventional methods.

Figure 1 Grubbs ruthenium catalysts used in metathesis

With the availability of well-defined metathesis catalysts (Figure [1]), olefin metathesis has become a useful tool in generating C–C bonds starting from relevant olefinic substrates. To design suitable precursors to olefin metathesis, one more critical reaction is generally used. In this context, we have compiled our own examples and have also selected some examples from the literature involving the assembly of complex targets with a metathesis sequence as a key step. Among the popular reactions, we found that olefination reactions, such as Wittig or related reactions, e.g., Petasis, Tebbe, and Peterson olefinations, in combination with metathesis can be used to generate carbocycles, macrocycles, and heterocycles. Alternatively, variations of Claisen rearrangements in tandem with metathesis are employed. Similarly, various allylation reactions have been used. Several cycloaddition reactions have been ingeniously coupled with a metathesis sequence. In addition, various other powerful C–C bond-formation reactions, such as the Baylis–Hilman reaction, Keck radical allylation, Grignard addition, Fischer indolization (FI), and diverse cross-coupling reactions have been used in tandem with metathesis. Several chiral auxiliaries have been employed to prepare optically active targets. Multicomponent reactions such as Ugi four-component reactions and Petasis three-component reactions have also been used in conjugation with metathesis to assemble intricate targets by using various Grubbs catalysts (Figure [1])

# 2

Olefinations

2.1

Petasis Olefination–Metathesis

Bennasar et al. reported a new synthetic approach to assemble 1,4-dihydroquinolines. By using a standard acylation technique, starting with 2-allylaniline (1), the necessary amide precursor 2 was easily prepared (Scheme [1]).[1] The acetanilide was then subjected to methylenation with a Petasis reagent to produce enamide 3. The enamide 3 was successfully isolated in a reproducible manner with 55% yield. Later, the enamide underwent ring-closing metathesis (RCM) on exposure to the G-II catalyst at 80 °C in toluene. The expected 1,4-dihydroquinoline 4 was obtained in 75% yield, demonstrating that the cyclization was unaffected by the steric environment of the enamide moiety. Finally, the 1,4-dihydroquinoline moiety was readily oxidized to give the corresponding aromatic product 5 in 80% yield.

Scheme 1 Synthesis of 1,4-dihydroquinolines by Petasis olefination and metathesis

# 2.2

Wittig Olefination–Metathesis

The key steps in this sequence are a Wittig reaction and RCM. In this regard, an aldehyde 6 was converted into a dialkene 8 through a Wittig reaction, and RCM of the dialkene intermediate 8 gave the cyclopentene core of the molecule (Scheme [2]). Basha’s procedure was then employed to convert the methylcarbamate-cyclopentene into a urea-cyclopentene 9. Later, halocyclization of the urea afforded the (dimethylamino)oxazoline ring 10 (83%) and, finally, a stereoselective alkene radical addition reaction followed by alkene isomerization and ozonolysis installed a hydroxymethyl group in position C-5.[2] This intermediate was finally converted into (–)-allosamizoline (11) in 94% yield after MOM deprotection with acid.

Scheme 2 Wittig reaction and RCM of the dialkene intermediate 8 to form the cyclopentene derivative 9. Reaction conditions: (a) EtMgBr, Et₃N, CH₂Cl₂, then Me₂NH, 24 h, 96%; (b) NIS, THF–H₂O, 10 h, 80%; (c) allyl(tributyl)tin, AIBN, benzene, 18 h, 81%; (d) trimethyl(vinyloxy)silane, G-II (5 mol%), 7 h, 100%; (e) O₃, CH₂Cl₂–MeOH, then NaBH₄, –78 °C, 3 h, 83%; (f) HCl, MeOH, 50 °C, 3 h, 94%.

# 2.3

Wittig Reaction–Metathesis

The synthesis of rebeccamycin, an antitumor antibiotic, relies on C–C bond formation between two indole units at C-2 and C-2′ in compound 12 (Scheme [3]).[3] This is one of the first examples involving metathesis to form an aromatic ring in one step. Normal Vilsmeier–Haack reaction conditions using the substrate 12 provided the desired dialdehyde 13 in 83% yield. Later, the N atoms were readily protected as carbamates. The aldehyde moieties were then converted into alkenes by using the Wittig reaction to give a diolefin, which, on exposure to the G-II catalyst, gave the desired indole-fused carbazole 15 in 64% yield.

# 2.4

Stille–Gennari Olefination–Metathesis

A chain elongation with the Stille–Gennari reagent, (F₃CCH₂O)₂P(O)CH₂CO₂Et, was used to obtain the (Z)-α,β-unsaturated ester 16 in 75% yield (Scheme [4]). Reduction of 16 with DIBAL-H afforded the corresponding allylic alcohol in 90% yield. The epoxide 17 with the required configuration was then prepared by a Sharpless asymmetric epoxidation with (–)-diethyl tartrate (DET)/Ti(O-i-Pr)₄/t-BuOOH (TBHP) in CH₂Cl₂ (85% yield), followed by oxidation with 2-iodoxybenzoic acid (IBX) in DMSO–CH₂Cl₂ and C₁ homologation with a Wittig reagent (Ph₃P=CH₂) (68% yield over the two steps) and treatment with tetrabutylammonium fluoride. Subsequent deprotection of the ether followed by an intramolecular ring opening of the epoxide in the presence of DDQ in CH₂Cl₂ gave the target molecule, decarestrictine (20) in 70% yield.[4]

Scheme 3 Indole-fused carbazole 15 by a Vilsmeier–Haack reaction and metathesis

Scheme 4 Stereoselective synthesis of decarestrictine (20). Reaction conditions: (a) DIBAL-H, CH₂Cl₂, –78 °C to r.t., 2 h, 90%; (b) DET, TBHP, CH₂Cl₂, –20 °C, 16 h, 85%; (c) IBX, DMSO, CH₂Cl₂, 0 °C to r.t., 2 h; then Ph₃PCH₂I, BuLi, THF, 100 °C to r.t., 2 h, 68%. (d) Bu₄NF, THF, r.t., 4 h, (e) DCC, DMAP, CH₂Cl₂, 0 °C to r.t.,10 h; 80%. (f) Grubbs II catalyst, CH₂Cl₂, reflux, 12 h; 65%. (g) DDQ, CH₂Cl₂/H₂0, 0 °C to r.t., 1 h; 70%.

# 2.5

Takai–Utimoto Olefination–Metathesis

In general, the reaction of allyloxy carbanions with carbonyl compounds occurs at the α-position, and this regiocontrol has been realized by using γ-alkoxy(allyl)indium reagents. An efficient exploitation of this protocol has been applied in generating a high yield of vic-diol mono ether 22 from the easily accessible allyl ethyl ether (21; Scheme [5]).[5] The alcohol group was then converted into an ester moiety in 23 by using acetyl chloride or acetic anhydride. Subsequently, a titanium-based olefination protocol, known as the Takai–Utimoto procedure, was performed to transform the substrate into the corresponding enol ether 24. Eventually, the G-II catalyst (10 mol%) was used to execute RCM followed by acid-catalyzed aromatization to furnish the 2,5-disubstituted furan 25 (51%).

Scheme 5 Synthesis of the 2,5-disubstituted furan 25 through olefination and metathesis

#
# 3

Rearrangement

3.1

Beckmann Rearrangement–Metathesis

From the easily available starting material dicyclopentadiene (26) and by applying a four-step synthetic sequence involving a Beckmann rearrangement and ring-rearrangement metathesis (RRM) as key steps, the tricyclic lactam 30 was produced in 90% yield (Scheme [6]).[6]

Scheme 6 Synthesis of aza-tricyclic compound 30 with a Beckmann rearrangement and RRM as key steps

# 3.2

Claisen Rearrangement–Metathesis

Starting with β-naphthol (31), a useful strategy has been realized to assemble spirocyclic skeletons. To assemble the target molecule, a Claisen rearrangement (CR) and an RCM sequence are critical steps in this process. β-naphthol (31) was O-allylated with potassium carbonate, acetone, and allyl bromide at r.t. to give the necessary starting material 32.[7a] Compound 32 was subjected to a CR under solvent-free microwave irradiation conditions to give 33, which was then subjected to a second round of O-allylation and CR to generate the gem-diallyl ketone 35; this underwent RCM in the presence of G-I catalyst to generate the spiro compounds 36 and 37 in yields of 34 and 19% (Scheme [7]).

Scheme 7 Synthetic strategy to generate spiro derivatives 36 and 37

A strategy for synthesizing the oxepine derivative 42 began with 6-bromo-2-naphthol (38) as a starting material. This was O-allylated using allyl bromide/K₂CO₃ in acetone to generate the O-allyl product 39 in 98% yield. Next, a microwave-assisted Claisen rearrangement of the allyl derivative 39 and subsequent O-allylation gave the diallyl derivative 41 in 93% yield.[7b] Finally, RCM was carried out to generate the oxepine derivative 42 in 96% yield (Scheme [8]).

Scheme 8 Synthesis of a naphthoxepin derivative through a Claisen rearrangement

# 3.3

Double-Claisen Rearrangement–RCM

Interesting strategies toward the synthesis of cyclophane derivatives involve a double-Claisen rearrangement (DCR) and RCM as key steps. Diverse cyclophane derivatives in which an alkene moiety connects the two phenolic moieties can be assembled by this method. Later, DCR and RCM protocols were found to be useful in designing various cyclophane derivatives.

To generalize this strategy, other cyclophane derivatives were synthesized by using readily available starting materials. For example, the bisphenol 43 was subjected to allylation with 3-bromoprop-1-ene to generate 44 in 92% yield (Scheme [9]). DCR of 44 gave diol 45, which was further methylated with methyl iodide to produce the corresponding dimethoxy derivative 46 (88%). Compound 46 was subjected to RCM with G-I or G-II catalyst to afford the ring-closure product 47 in 56% yield.[7c]

Scheme 9 Synthesis of the cyclophane derivative 47 by CR and RCM.

Kotha and Mandal have demonstrated a useful benzoannulation strategy that involves DCR followed by a one-pot RCM and a DDQ oxidation sequence (Scheme [10]).[8] Initially, 1,4-dihydroxyanthra-9,10-quinone (48) was O-allylated to produce substrate 49 in 81% yield as a necessary diallyl precursor for the DCR. The anticipated double-Claisen-rearranged product 50 was obtained in 71% yield when the bisallyloxyanthraquinone 49 was treated with sodium dithionate in the presence of sodium hydroxide in 1:1 DMF–H₂O at 130 °C. The methylated intermediate 51 was produced in 98% yield by protecting the hydroxyl groups, and subsequent RCM and DDQ oxidation steps were performed to generate the aromatized benzoannulated product 52 in 49% yield.

Scheme 10 Benzoannulation strategy involving DCR and RCM

# 3.4

Double-Claisen–retro-Diels–Alder–Metathesis

A simple approach to 1,4-quinone derivatives such as 56 (Scheme [11]) was realized by combining RCM with atom-economic processes such as the Claisen rearrangement (CR) and rDA reactions.[9] The synthetic approach started with the preparation of the DA adduct 53. Under THF reflux conditions, cycloadduct 53 was allylated with allyl bromide in the presence of NaH to produce the O-allyl aromatized product 54 in 56% yield. Next, to realize the CR, compound 54 was heated in a pressure tube along with C-allylated product (19%) at 180 °C in 1,2-dichlorobenzene as the solvent to generate 2,3-diallyl-1,4-naphtho-1,4-quinone (55) in 91% yield. The formation of the diallylquinone 55 proceeded through DCR along with an rDA reaction of the diallyl precursor 54. Anthra-9,10-quinone (56) was then produced in 91% yield by RCM of 55 in the presence of G-I catalyst at ambient temperature.

Scheme 11 Synthetic approach to anthra-9,10-quinone (56)

# 3.5

Tandem Claisen–Metathesis

A tandem Claisen rearrangement/Wittig olefination/E/Z-isomerization/cyclization sequence was used to generate the coumarin derivative 59.[10] The precursor 57 was treated with ethyl (triphenylphosphoranylidene)acetate under MW irradiation conditions (Scheme [12]). As a result, CR also occurred, leading to the rapid production of the coumarin derivative 58 in 82% yield. Subsequently, the expected cross-metathesis product 59 was obtained in a good yield (82%).

Scheme 12 Coumarin synthesis by Claisen rearrangement, Wittig reaction, and cross-metathesis

# 3.6

Aryne Aza-Claisen Rearrangement–Metathesis

By treating substrates 60 and 61 in the presence of CsF in acetonitrile, the intended product N,2-diallyl-N-phenylaniline (62) was generated in 81% yield (Scheme [13]).[11] Here, a benzyne derivative is involved in the generation of intermediate 62a. The diallylamine 62 then underwent RCM in the presence of HG-II catalyst in CH₂Cl₂ to give the benzo-fused seven-membered heterocyclic product 1-phenyl-2,5-dihydro-1H-benzo[b]azepine (63) in 65% yield.

Scheme 13 Aryne aza-Claisen rearrangement and metathesis to generate a benzazepine

# 3.7

Aza-Claisen Rearrangement–Metathesis

By means of an aza-Claisen rearrangement of the trichloroacetimidate derivative 64 in THF with bis(acetonitrile)palladium(II) chloride as the catalyst, the erythro- and threo-allylic trichloroamides 65a and 65b were produced in a 12:1 ratio in 52% yield (two steps) (Scheme [14]).[12a]

A noncoordinating solvent (toluene) improved the stereochemical outcome of this directed rearrangement, giving 65a and 65b in 55% yield and 16:1 ratio. Flash column chromatography was used to isolate the desired major isomer 65a from the mixture. These findings showed the value of switching to a noncoordinating solvent in improving the ability of the Pd(II) catalyst to increase the diastereoselectivity. After completing this first crucial step, the synthesis of (+)-R-conhydrine was continued with the protected amine 66 containing a suitable protecting group. Subsequent rearrangement followed by N-alkylation gave a diene that underwent an RCM process to generate the piperidine ring. At this point, a change in the protecting group was required because of earlier attempts to alkylate 65a produced the recovered starting material. Thus, the product 66 was isolated in a good yield by sequential hydrolysis and acylation with but-3-enoyl chloride. A G-I catalyst-induced RCM of 66 resulted in a quantitative yield of the unsaturated lactam 67. Finally, (+)-(R)-conhydrine (68) was produced in 42% yield by hydrogenating the alkene, reducing the lactam with borane-THF, and deprotecting the hydroxy group under acidic conditions.

Scheme 14 Synthesis of (+)-(R)-conhydrine by an aza-Claisen rearrangement and metathesis

# 3.8

Aza-Claisen Rearrangement–Metathesis

Scheme 15 Aza-CR and RCM to produce a cyclohexene derivative

2,2,2-Trichloro-N-[(1R)-cyclohex-2-en-1-yl]acetamide (70) was successfully synthesized by a one-pot, tandem reaction with palladium(II)-catalyzed aza-Claisen rearrangement and an RCM as key steps (Scheme [15]).[11] [12] The target compound was obtained in an excellent yield and with good enantiomeric excess when a chiral Pd(II) catalyst such as (S)-COP-Cl was used during the rearrangement process.

# 3.9

Reformatskii–Claisen–Metathesis

Aldehyde 71 was subjected to Wadsworth–Emmons condensation with ethyl diethylphosphonoacetate to provide the corresponding ester (Scheme [16]).[13] Several steps, followed by reduction of the ester with DIBAL-H and condensation with ClCF₂CO₂H produced the allyl ester 72 in good yield. Ester 72 was then subjected to a silicon-induced Reformatskii–Claisen reaction: a mixture of ester was treated with chloro(trimethyl)silane and freshly activated zinc in dry acetonitrile at 105 °C for 24 hours to give allylic ester 73. The crude product was converted into the desired gem-difluorinated esters 78–81 (syn/anti 3:1) in a straightforward manner, and their structures were determined by ¹⁹F NMR.

Scheme 16 Stereoselective synthesis of 3,3-difluoro-2-hydroxycyclopent-1-ene derivatives by Claisen rearrangement and RCM. Reaction conditions: (a) (i) (EtO)₂POCH₂CO₂Et, NaH, THF, (ii) AcOH–H₂O, (iii) Ag₂O, BnBr, CH₂Cl₂, (64%, 3 steps); (b) DIBAL-H, CH₂C1₂, –78 °C (99%); (c) ClCF₂CO₂H, CHCl₃, 90 °C (87%); (d) (i) Zn, TMSCl, MeCN, 105 °C, (ii) EtOH, H₂SO₄, 50 °C, (72%, 2 steps); (e) MeNHOMe, BuLi, THF, –78 °C; (f) (i) allylmagnesium chloride, THF, –78 °C, (ii) Et₃N, THF; (g) NaBH₄, CeCl₃·7H₂O, MeOH, 0 °C; (h) G-II, toluene, 100 °C.

# 3.10

Ireland–Claisen–Metathesis

An Ireland–Claisen rearrangement was employed to generate the dienes 83a and 83b from the allylic ester 82 (Scheme [17]).[14a] [b] The stereochemical outcome was significantly influenced by the reaction conditions. Subsequently, an RCM reaction was used to form the cyclohexene ring products 84a and 84b, leading to an enantioselective synthesis of (+)-pancratistatin.

Scheme 17 Enantioselective synthesis of a (+)-pancratistatin intermediate

A total synthesis of a sequosempervirin A derivative with a distinctive spirocyclic structure by using an orthoester Claisen rearrangement and RCM process has been reported by Maity and Ghosh (Scheme [18]).[14c] The strategy commenced with an orthoester Claisen rearrangement of allylic alcohol 85 at 140 °C to produce the unsaturated ester 86 in 66% yield. Alkylation of the lithium enolate generated from the ester with p-methoxybenzyl bromide (PMBBr) afforded the corresponding ester in an excellent yield. The ester was then transformed into an aldehyde derivative through reduction (LiAlH₄) and Swern oxidation. Addition of vinylmagnesium bromide to the aldehyde gave a single diastereomer of the dienol 87 in 80% yield. RCM of dienol 87 with G-I catalyst (4 mol%) proceeded smoothly to give the spirocycle 88 in 81% yield. The cis-orientation of the hydroxy and p-methoxybenzyl groups in the spirocycle was indicated by the ¹H NMR coupling constant (J = 6.3 Hz) of the proton adjacent to the hydroxy group, thereby confirming the stereochemical assignment for the dienol.

Scheme 18 Toward a total synthesis of sequosempervirin A. Reactions conditions: (a) LDA, PMBBr, THF, 0 °C, 93%; (b) (i) LiAlH₄, Et₂O, 0 °C to r.t., 1 h, 88% (ii) oxalyl chloride, DMSO, Et₃N, CH₂Cl₂, –78 °C, 73%; (c) vinylmagnesium bromide, THF, 0 °C, 1 h, 80%.

# 3.11

Overman Rearrangement–Metathesis

The 1β-dicyclopentadienol 89 was used to generate the trichloroacetimidate 90 by treatment with trichloroacetonitrile with DBU as a base (Scheme [19]).[15] Then, under toluene reflux conditions, the crude trichloroacetimidate 90 underwent an Overman rearrangement to produce the rearranged trichloroacetamide 91a and amine 91b in yields of 41 and 27%, respectively. Subsequent hydrolysis of compound 91a with 2 N NaOH, gave the allylic amine 91b in 54% yield. Next, the RRM precursor 92 was produced in 96% yield by N-allylation of amine 91b with NaH as a base in DMF. In the presence of a G-I catalyst and under an ethylene environment, the allyl derivative 92 underwent an RRM sequence to give the azatricyclic product 93 in 98% yield.

Scheme 19 Overman rearrangement and RRM to obtain the aza-tricyclic product 93

# 3.12

Overman Rearrangement/Tandem RCM/Intramolecular Kharasch Reaction

Sutherland and co-workers reported a tandem process for the synthesis of a bicyclic γ-lactam (Scheme [20]).[16] Here, bis(acetonitrile)palladium(II) chloride (10 mol%) was used to perform an Overman rearrangement of 94 to give the diallyl compound 95. RCM of 95 was carried out at 60 °C in the presence of G-I catalyst (10 mol%), A Kharasch cyclization was then accomplished by raising the temperature to 155 °C, which resulted in the isolation of the bicyclic lactam 96 as a single diastereomer in 87% yield.

Scheme 21 Synthesis of tetrakis-fused-benzofurans, 2H-chromenes, and benzoxepine derivatives

# 3.13

Four Directional Claisen Rearrangement–Metathesis

Scheme 20 Synthesis of bicyclic lactam 96

A useful approach to the assembly of a library of multidirectional O-heterocycles based on a rigid, tetrahedral core was reported by Kotha and Solanke (Scheme [21]).[17] New derivatives of tetraphenylmethane were synthesized by employing a Claisen rearrangement and RCM as key steps. Mono-, di-, tri-, and tetrasubstituted benzofurans, 2H-chromenes, and benzoxepine derivatives were synthesized successfully by this strategy. To prepare the annulated furan derivative 99, allylation, CR, isomerization and RCM were used as key steps. A tactical use of these steps similarly gave the six- and seven-membered annulated heterocycles 105 and 102, respectively.

# 3.14

Aza-Claisen–Metathesis

Benzazepine derivatives can be obtained by following a simple approach involving an aza-Claisen rearrangement and RCM as key steps.[18] Treating the diallyl derivative 109 with G-II catalyst gave the 7-substituted 2,3,4,5-tetrahydro-1-benzazepine derivative 110 in a good yield (90%) (Scheme [22]).

#
# 4

Allylation

4.1

N-Allylation–Metathesis

N-Allylation of the amino acid derivative 112 was achieved by refluxing with 4-bromobut-1-ene and K₂CO₃ in acetonitrile (Scheme [23]).[19] Similarly, the required dialkenylated compound 117 was obtained through N- and C-allylations of 115. The cyclic amino acid derivatives 114 and 118 were then obtained through ruthenium-catalyzed RCM reactions of 113 and 117, respectively, in good yields of 92 and 83%. The RCM reaction utilized G-II catalyst in dry CH₂Cl₂ at room temperature under high-dilution conditions. The structures of products 113 and 114 were confirmed by the presence of distinctive signals for a terminal olefin moiety and a –CH group (δ = 5.8) and by the absence of a signal for an –NH moiety in the ¹H NMR spectra.

# 4.2

N-Allylation of Glycoluril Derivatives–Metathesis

For the tetra-N-allylation of glycoluril derivatives 119–121 under mild conditions, unlike those in an earlier report, the reaction was performed in acetonitrile in the presence of a weak base such as cesium carbonate (5 equiv) and allyl bromide (4.50 equiv) to afford the corresponding tetraallyl products 122–124 in six hours as single products in yields of 57–68% (Scheme [24]).[20] The tetraallyl product 122 was then subjected to RCM using G-I catalyst in anhydrous CH₂Cl₂ at r.t., resulting in a low yield of the RCM product 125 (25%). However, addition of a catalytic amount of Ti(O-i-Pr)₄ was found to be useful in generating the RCM products in improved yields, and this gave products 125–127 in yields of 68–77% within a shorter reaction time of 12 hours.

# 4.3

Diallylation of Kotha–Schölkopf Glycine Equivalent–Metathesis

A bisallylation sequence was attempted under phase-transfer catalyst (PTC) conditions (tetrabutylammonium hydrogen sulfate) using ethyl isocyanoacetate (128) as a glycine equivalent in acetonitrile with potassium carbonate as a base (Scheme [25]).[21] Two equivalents of the allyl bromide reacted with ethyl isocyanoacetate (128) to produce a mono- and diallylated product. Because the monoallylated product was relatively volatile, its precise yield could not be established. However, by treating ethyl isocyanoacetate (128) with an excess of allyl bromide (3 equiv) under PTC conditions, the diallyl product 130 was produced in an excellent yield (86%) instead. Even in a refrigerator, these isonitrile compounds tended to decompose. Interestingly, however, their acetylated derivatives could be stored for extended periods. The isonitrile derivative 129 was therefore hydrolyzed immediately in the presence of 1 N HCl in EtOH and protected as the acetyl derivative 130, which underwent RCM in the presence of G-I catalyst in toluene to give the cyclic amino acid derivative 131.

Scheme 23 Synthesis of cyclic amino acid products by olefin metathesis

Scheme 24 Synthesis of glycoluril derivatives using RCM as a key step

Scheme 25 Preparation of the cyclic amino ester derivative 131

# 4.4

O’Donnell Schiff Base–Metathesis

The O’Donnell Schiff base 132 was allylated using potassium carbonate in refluxing acetonitrile (Scheme [26]).[22] Subsequent hydrolysis of the allylated Schiff base 132 with 1 M HCl led to the amino ester 133, the NH₂ group of which was protected as a tosyl derivative to produce product 134 in 78% yield. The enyne building block 135 was then prepared in quantitative yield (98%) by N-propargylation with propargyl bromide. When this enyne building block was treated under metathesis conditions using G-I catalyst, the inner–outer-ring diene 136 was obtained in 65% yield; this product is useful for a DA strategy.

Scheme 26 Preparation of inner–outer-ring diene 136

# 4.5

C-Allylation of Barbituric Acids–Metathesis

The 1,3-dimethyl derivative of barbituric acid 137 was dialkenylated using benzyl(triethyl)ammonium chloride (BTEAC) as a phase-transfer catalyst to produce the diallyl product 138 in 83% yield (Scheme [27]).[23] An RCM sequence with the diallyl product 138 was carried out with G-I catalyst to produce the expected spiroannulated derivative 139 in a good yield (88%).

Scheme 27 Synthesis of the spiro-annulated barbituric acid derivative 139

# 4.6

O-Allylation–Metathesis

Scheme 28 Tricyclic system as a cis/trans-olefinic mixture

Scheme 29 Synthesis of C ₃-symmetric oxepines 152 and 153 containing phenyl or triazine moieties

Scheme 30 Preparation of an enantioenriched spiro compound by RCM

The cis-decalin derivative 140 was used to produce the 3,8-dioxapropellane derivative 143 (Scheme [28]).[24] This was accomplished by reducing the diester 140 with LAH to create the diol 141 (92%). cis-9,10-Bis(allyloxymethyl)decalin (142) was then produced in a high yield (74%) by O-allylation of the diol 141 with allyl bromide in the presence of NaH. RCM of the diallyl derivative 142 in the presence of the G-I catalyst gave the tricyclic system 143 as a cis/trans-olefinic mixture with a 73% yield.

In the presence of K₂CO₃ in acetone, 1,3,5-tris(4-hydroxyphenyl)benzene (144) and 2,4,6-tris(4-hydroxyphenyl)-1,3,5-triazine (145) were treated with allyl bromide to produce the corresponding O-allyl derivatives 146 and 147 in yields of 90 and 93%, respectively (Scheme [29]).[25] The triallyl compounds underwent Claisen rearrangement in o-dichlorobenzene or diphenyl ether as a solvent at 220 °C to give the rearranged products 148 and 149 in yields of 56 and 58%, respectively. Later, by treating the rearranged phenols with allyl bromide in the presence of K₂CO₃ in acetone at r.t. for 6 h, we were able to synthesize the hexaallyl derivatives 150 and 151 in yields of 82 and 83%, respectively. Additionally, after optimizing the experimental conditions, we treated the rearranged allyl ether derivatives 150 and 151 with G-I or G-II catalyst (10 mol%) to give the C ₃-symmetric oxepines 152 (81%) and 153 (86%) containing phenyl and triazine moieties, respectively.

# 4.7

Allylation with Schölkopf Chiral Auxiliary–Metathesis

The geminally attached diolefinic compound 156, produced from (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (154), served as a useful template to build unusual amino acid derivatives by an RCM sequence (Scheme [30]).[26] The isopropylpyrazine 154 was subjected to a stepwise bisalkylation, permitting the introduction of two distinct moieties. Lithiation at –78 °C was used to perform the first alkylation step to introduce allyl, 4-bromobut-l-enyl, or 5-bromopente-l-enyl substituents. The resulting monoalkylated products were obtained in yields of 80 to 92%, and the diastereomeric excess varied from 75 to 96%. Flash chromatography was used to isolate the isomers; however, this separation is not necessary, because the second alkylation step determines the overall stereochemistry of the reaction sequence. The monoalkyl compounds underwent a second slower lithiation at –50 °C and the second alkylating agent was introduced after cooling the lithiated species to –78 °C. The stereochemistry at the initial alkylating site is lost after the second lithiation. The carbanionic center at the 5-position is created by the new alkylating agent entering from the side of the ring opposite the isopropyl group. RCM of substrate 156 gave the cyclopentane derivative 157, which could be hydrolyzed under mild conditions to give the corresponding amino ester.

# 4.8

Tsuji–Trost Allylation–Metathesis

From the corresponding β-dicarbonyl compounds 158 and 161, the spirocyclic systems 160 (77%) and 163 (77%) were produced by allylation followed by RCM, where the RCM was realized by using G-I catalyst (Scheme [31]).[27] Both the allylations were catalyzed by a palladium(0) complex.

Scheme 31 Combining a Trost allylation and RCM to generate spiro compounds

# 4.9

Evans–Tishchenko Reaction

A novel strategy involving a sequential Evans–Tishchenko reaction and an RCM-based protocol has been reported for the synthesis of medium-ring lactones.[28] The Evans–Tishchenko reaction of unsaturated aldehydes with the unsaturated hydroxy ketone 165 exhibits a high diastereoselectivity (>95:5), and the conditions for the RCM process of the resulting olefins have been optimized to generate high yields of medium-ring lactones. The creation of the fully functionalized core of octalactin A serves as evidence of the synthetic utility of this strategy. Under moderate conditions involving a Horner–Wadsworth–Emmons reaction, the β-ketophosphonate 164 and isovaleraldehyde were condensed to produce a protected enone (Scheme [32]). Then, treatment with HF in acetonitrile was used to regenerate the β-hydroxy enone 165 from the protected enone. An Evans–Tishchenko coupling of 165 to hex-5-enal gave the monoesterified product 166 in excellent yield (93%) and with good diastereoselectivity (90:10 anti/syn). The unsaturated lactone 167 was prepared by RCM of the unprotected substrate 166 using G-II catalyst. The minor byproduct 168, which was identified by close inspection of ¹H NMR spectral data of the isolated material, was assumed to have been formed by competitive metathesis of the trisubstituted double bond.

Scheme 32 RCM strategy using a nonfunctionalized β-hydroxy enone

# 4.10

Alkenylation with Evans’s Chiral Auxiliary–Cross-Metathesis

The oxazolidinone derivative 170 was assembled by coupling hex-5-enoic acid (169) with the Evans chiral auxiliary using a mixed anhydride (Scheme [33]).[29] The equivalent 2-methylhex-5-enoic acid derivative 171 was produced by alkylating the sodium enolate of the hexenoic acid derivative with methyl iodide. Alkenol 172 was then produced in 62% yield from 171 through reductive elimination of the chiral auxiliary by treatment with lithium borohydride in methanol. By treatment with NaH and p-methoxybenzyl chloride, the hydroxy group of 172 was protected as a p-methoxybenzyl ether to give the derivative 173. By performing CM reaction using methyl acrylate and the G-II catalyst in hot toluene, it was possible to extend the chain of 173 at the alkene terminal to give a 95% yield of enoate 174. Enoate 174 was asymmetrically dihydroxylated with ADmix-α in tert-BuOH–H₂O, and a respectable yield of the dihydroxy ester was produced. A 1,3-dioxolane was then produced by treating the diol with 1,3-dimethoxypropane in the presence of a catalytic quantity of TsOH. The C₁–C₇ fragment of gulmirecin B was realized by a redox sequence involving Swern oxidation of the aldehyde and reduction of the ester group with LiAlH₄; subsequent protection gave the final product 175.

Scheme 33 Synthesis of an oxazolidinone derivative by using Evan’s chiral auxiliary and a cross-metathesis. Reaction conditions: (a) ADmix-a, t-BuOH–H₂O, 0 °C to r.t., (b) TsOH, rt, 71% (c) LiAlH₄, THF, 0 °C to r.t., 96% (d) DMSO, (COCl)₂, CH₂Cl₂, Et₃N, –78 °C, 95%

# 4.11

Maruoka Allylation–Metathesis

By using the chiral titanium complex (R,R)-I and allyl(tributyl)tin, the aldehyde 176 was converted through an enantioselective Maruoka allylation into the homoallylic alcohol 177 in 86% yield with good enantioselectivity (98% ee) (Scheme [34]).[30] The resulting homoallylic alcohol 177 was orthogonally protected as its MOM ether 178 (90% yield) by treatment with MOMCl in the presence of N,N-diisopropylethylamine base in CH₂Cl₂. The corresponding CM product 179 was successfully produced in 80% yield by treating precursor 178 with 3-benzyloxybut-1-ene in the presence of G-II catalyst (5mol%) in refluxing dichloromethane.

Scheme 34 Enantioselective Maruoka allylation produced homoallylic alcohol 179

# 4.12

Arbuzov Reaction (P-Allylation)–Metathesis

Under Arbuzov reaction conditions, triethyl phosphite and allyl bromide gave the corresponding allyl phosphonate 180a (Scheme [35]),[31] which underwent selective monochlorination with oxalyl chloride to give the phosphonochloridate 180 in 97% yield. The metathesis precursor 181 was then produced in a 67% yield by a subsequent reaction with allyl alcohol. An RCM reaction using G-I catalyst in refluxing dichloromethane successfully gave the ring-closed phosphonate 182 in 87% yield.

#
# 5

Cycloadditions

5.1

[2+2]/[6+2] Photocycloaddition–Metathesis

The diallyl quinone 183 (Scheme [36]) was produced by a four-step process involving a DA reaction.[32] Diallylation of hydroquinone, followed by a Claisen rearrangement, resulted in the 1:1 rearranged allylated hydroquinone; subsequent oxidation of the 2,3-diallyl derivative with MnO₂ gave the DA precursor. The 1,4-benzoquinone DA adduct 183 was then generated by cycloaddition of the quinone with cyclopenta-1,3-diene at 0–10 °C. The DA adduct 183 was then subjected to a [2+2] photochemical reaction induced by UV light to give the pentacyclic dione 184 (80%), which underwent an RCM sequence in the presence of G-I catalyst to give 90% yield of the hexacyclic propellane 185. As an alternative, compound 188 was prepared by a different route that included the RCM, aromatization, and [6+2] photocycloaddition.

Scheme 35 Arbuzov reaction yielded ring-closed phosphonate 182

Scheme 36 Synthesis of hexacyclic propellanes 185 and 188 by RCM and photocycloaddition

# 5.2

[2+2+2] Cyclotrimerization–Metathesis

Hepta-1,6-diyne (189) underwent a [2+2+2] cyclotrimerization with dimethyl acetylenedicarboxylate (DMAD) to produce the annulated alkynylbenzene derivative 190 (44%), which, on CM with ethylene in the presence of G-II catalyst, gave diene 191 in 85% yield, useful as a precursor for DA reactions (Scheme [37]).[33]

Scheme 37 An alkynylbenzene derivative by [2+2+2] cyclotrimerization

# 5.3

Macmillan Catalyst-Promoted Diels–Alder Reaction {[4+2] Cycloaddition}–Metathesis

To create a suitable precursor to assemble aburatubolactam A, Henderson and Phillips used a Macmillan catalyst-promoted DA reaction and metathesis sequence.[34] They began by preparing the bicyclo[2.2.1]heptene system and then used a ring rearrangement–metathesis (RRM) sequence involving the G-I catalyst to give the bicyclic ketone 194 (Scheme [38]). The precursor 192 was prepared in 65% yield by a DA reaction of (4E)-hex-4-en-3-one and cyclopentadiene in the presence of MacMillan's catalyst A. The DA adduct 192 was then converted into enone 193 (80%). To obtain the necessary bicyclo[3.3.0]octane derivative 194, enone 193 was treated with G-I catalyst under an ethylene environment to give the RRM product in 90% yield.

Scheme 38 Synthesis of 194, a precursor for aburatubolactam A by RRM

#
# 6

Coupling Reactions

6.1

Heck Coupling–Metathesis

Pd-catalyzed arylation of the diene 196 favored C–C bond formation at the 1,3-diene system’s less sterically constrained end (Scheme [39]).[35] An enyne metathesis of 195 followed by a Heck coupling of 196 gave the tricyclic product 197 in 53% yield.

Scheme 39 Heck coupling to form a tricyclic product

# 6.2

Suzuki–Miyaura Coupling–Metathesis

(4-Formylphenyl)boronic acid (199) was coupled with 1,3-bis(bromomethyl)benzene (198) under Suzuki coupling reaction conditions to yield the cross-coupling product 200 (80%) (Scheme [40]).[36a] [b] The presence of a palladium(0) catalyst [Pd(PPh₃)₄] facilitated the cross-coupling reaction with good efficiency. Allylation of the dialdehyde 200 with allyl bromide in the presence of indium provided 201, a suitable precursor for cyclophane synthesis. Subsequent exposure of the diolefin 201 to RCM using G-I catalyst led to a complex mixture; this reaction was then improved by using G-II catalyst to obtain the cyclophane derivative 202 in a 33% yield as a 2:1 mixture of diastereomers. The formation of oligomeric byproducts during the macrocyclization might have contributed to the reduced overall yield.[36c] Subsequent PCC oxidation of cyclophane 202 produced the dione 203 in 76% yield.

Scheme 40 Synthesis of a cyclophane with a Suzuki cross-coupling and metathesis as key steps

Scheme 41 RCM of an isomerized olefin leads to a tetracyclic molecule

Several routes have been reported for the synthesis of angucyclines, due to their significant biological activity and intricate structural features (Scheme [41]). De Koning and his team reported a useful approach for constructing the benzanthracene moiety by employing a Suzuki–Miyaura coupling reaction and RCM as key steps.[36d] The bromonaphthalene derivative 206 underwent a Suzuki coupling reaction with 2-(formylphenyl)boronic acid to give the cross-coupling product 208 in 60% yield. Aldehyde 208 was then subjected to Wittig olefination to produce the corresponding alkene 209 (88%), which was further treated with t-BuOK in THF to generate the isomerized product 210. Subsequently, RCM of the isomerized olefin 210 with G-II catalyst gave the ring-closure product 211 (85%). The final step involved the use of CAN to oxidize the hydroxy derivative to produce the desired tetracyclic quinone 212 in 76% yield.

A Suzuki–Miyaura cross-coupling and RCM were also used as the main steps in a synthesis of the 7-substituted benzazepine derivative 216 (72%) (Scheme [42]).[18] [36d]

Scheme 42 Benzazepine derivative synthesis by Suzuki coupling and RCM

# 6.3

Peptide Coupling–Metathesis

The synthesis of the peptides 218 and 219 involved an on-bead strategy, with the incorporation of two O-allyl residues for subsequent RCM (Scheme [43]).[37] Removal of the on-bead-assembled peptide from the resin with simultaneous deprotection of the side-chain protecting groups under standard conditions gave the linear octapeptide derivative 219. Initial efforts to carry out on-resin RCM proved unsuccessful. Instead, the fully side-chain-protected linear peptides were cleaved from the resin under mild acidic conditions (1,1,1,3,3,3-hexafluoroisopropanol, CH₂Cl₂), affording compounds that were soluble in organic solvents. RCM proceeded smoothly in the presence of G-II catalyst in CH₂Cl₂ to give the tethered peptide 220 as a mixture of 1:4 mixture of the cis- and trans-isomers (as determined by ¹H NMR analysis).

Scheme 43 Solid-phase synthesis of a peptide and its metathesis

# 6.4

Hiyama Coupling–Metathesis

[(E)-2-(4-chlorophenyl)vinyl](triethoxy)silane (223) was obtained by CM of 4-chlorostyrene (221) with the vinylsilane 222 in the presence of G-II catalyst, or by silylative coupling of the same parent compounds (Scheme [44]).[38] Olefin 223 was then used in the synthesis of 4-chlorostilbene (224) in 85% yield through a palladium-catalyzed Hiyama coupling reaction with iodobenzene.

Scheme 44 Synthesis of 4-chlorostilbene by a palladium-catalyzed Hiyama coupling

#
# 7

Grignard Reaction

7.1

Grignard Reaction–Fischer Indolization–Metathesis

By using a Grignard addition, Fischer indolization (FI), and RCM sequence, a hybrid cyclophane containing bisindole-thiophene moiety 229 was generated (Scheme [45]).[39] The synthetic strategy started with Grignard addition to thiophene-2,5-dicarbaldehyde (225) to give the dihydroxy derivative 226 as a diastereomeric mixture (52%), which was further oxidized to produce the RCM precursor 227 (73%). However, an RCM sequence was not realized when the compound 227 was treated with G-II catalyst, possibly because the sulfur atom that is present in the bisolefin 227 can coordinate with the G-II catalyst. An FI of dione 227 gave the bisindole 228. The rigidity generated during the bisindolization facilitated partial shielding of the sulfur atom, and the indole components brought the alkene groups much closer together, facilitating ring closure. Thus, when diene 228 containing two indole moieties was treated under metathesis conditions, the cyclophane 229 was obtained successfully in 90% yield.

Scheme 45 Systematic strategy for the synthesis of the bisindole-thiophene containing cyclophane 229. l-(+)-TA = l-(+)-tartaric acid; DMU = 1,3-dimethylurea

2,3,4,9-Tetrahydro-1H-carbazole (232) was obtained through FI of cyclohexanone (230) with phenylhydrazine hydrochloride (231) (Scheme [46]).[39b] A subsequent regioselective oxidation of carbazole 232 (80%) with periodic acid resulted in the formation of the keto carbazole derivative 233 (65%). Keto carbazole 233 was then subjected to N-allylation at room temperature, followed by Grignard addition, leading to the formation of a diallyl carbazole derivative 235 in 72% yield. Unfortunately, the desired ring-closure product 236 was not obtained on treatment with 5 mol% G-I catalyst. However, a successful synthesis of azepinocarbazole 236 was achieved in 70% yield by treating the RCM precursor 235 with the G-II catalyst (5 mol%).

Scheme 46 Preparation of an azepinocarbazole derivative using a Fischer indolization and RCM

# 7.2

Grignard Reaction–Metathesis

In this strategy, the synthesis of the symmetrical spiro 1,3-bisketone 240 was conceived (Scheme [47]).[39c] [40b] To this end, dialkenylation of commercially available diethyl malonate (237) with allyl bromide in aqueous NaOH in the presence of benzyl(triethyl)ammonium chloride (BTEAC) as a phase-transfer catalyst delivered the dialkenylated compound 238 in 95% yield. Compound 238 was then treated with vinylmagnesium bromide, and we observed a 1,4-addition of a vinyl group to the α,β-unsaturated carbonyl compound formed by the replacement of the ethoxy group of compound 238 to afford tetraene 239 (47% yield). Interestingly, vinyl group addition was observed during a vinyl Grignard reaction without any additive, i.e., the 1,4-addition occurred in the absence of a copper catalyst. Subsequent RCM of compound 239 gave the symmetrical compound 240 and the partially ring-closed product 241.

Scheme 47 Symmetrical spiro 1,3-bisketone synthesis by a Grignard addition and RCM strategy

Scheme 48 Synthesis of extended cage polycyclic systems

The Grignard addition and RCM strategy was also extended to cage polycyclic systems. In this regard, a Grignard reagent reacted with hexacyclic dione 242 at 0 °C to produce the desired diallylic compound 243 in 88% yield (Scheme [48]).[39c] [40a] The Grignard reagent is typically present as a mixture of dimeric, trimeric, and polymeric components at higher concentrations (1.0 M solution), but this can be prevented by using a freshly prepared Grignard reagent at a low concentration (0.1 M solution). The presence of the monomeric form of the Grignard reagent at a low concentration might facilitate the formation of diol 243. Additionally, the diol 243 was also produced when the diketone was combined with an excess of the Grignard reagent, which concurrently attacked the carbonyl groups in the diketone 242. The tetraallyl compound 244, along with the triallyl derivative 246 as a minor product, were then produced by subjecting the diallyl diol 243 to an O-allylation procedure. The G-I catalyst was used to perform an RCM sequence on the tetraallyl compound 244 (53%) in dry dichloromethane at r.t. However, this reaction was found to be sluggish, and an optimization of the reaction conditions was needed. Use of the G-I catalyst in refluxing toluene turned out to a useful set of conditions to produce the double-ring-closure product 245 in 85% yield. Similarly, the mono-ring-closure product 247 (66%) was obtainable from 246 by adopting the optimized conditions.

The Grignard addition product 249 was produced in 96% yield when pyridine-2,6-dicarbonitrile (248) was treated with the Grignard reagent hex-5-en-1-ylmagnesium bromide (Scheme [49]).[39c] RCM was then used to create the cyclophane derivative 250 as the E-isomer.

Scheme 49 Grignard and RCM strategy for creating the (E)-cyclophane derivative 250

An interesting class of sulfur-containing cyclophanes (thiacyclophanes) were readily prepared by using Grignard addition and RCM (Scheme [50]).[40d] Thus, the dialdehyde 251 was subjected to Grignard addition with allylmagnesium bromide to produce the bis(hydroxyallyl) compound 252 in 81% yield. A subsequent ring closure gave the thiacyclophane 253; several sets of conditions were tested with G-I, G-II, and GH-II catalysts, but this step turned out to be more difficult than expected and became a bottleneck in the proposed strategy. However, after several attempts, it was found that the optimized condition appeared to involve using G-II catalyst (10 mol%) along with a Lewis acid [Ti(O-i-Pr)₄] as an additive, giving the thiacyclophane 253 in 24% yield. In the presence of PCC in CH₂Cl₂, the product 253 was oxidized to give the dione 254 in 86% yield. This strategy was further extended to an elegant synthesis of dithiacyclophanes by ring closure, giving, for example, a 63% yield of the E-isomer of the dithiacyclophane 259.

Scheme 50 Approach to thiacyclophanes by Grignard addition and RCM

#
# 8

Radical reactions

8.1

Tandem RCM–Intramolecular Kharasch Addition Reaction Sequence

Acyclic diene precursor 260 was converted into the bicyclic [3.3.0] ring structure 261 in a single step (Scheme [51]).[12] [16] [41] At ambient temperature, the metathesis reaction created the five-membered-ring compound 261 (75%). Under less forceful conditions, (60 °C vs 155 °C) a Kharasch addition of the N-tosylated derivative 262 gave the five-membered lactam 263 in 63% yield. The outcome relies on an atom-transfer radical mechanism over an oxidative addition/reductive elimination pathway involving ruthenium. It is intriguing to note that the Kharasch addition is made easier by the addition of the tosyl group to the amide functionality; the reaction proceeds at a lower temperature, but takes longer to complete. Furthermore, on changing the trichloroacetamide to the matching tribromoacetamide, the Kharasch reaction became more efficient.

Scheme 51 Kharasch addition to create the five-membered rings 261 and 263

# 8.2

Tandem RCM/Intramolecular Kharasch/Intermolecular Kharasch

Scheme [52] shows an expanded tandem procedure that incorporates both intra- and intermolecular Kharasch additions.[41] On heating diene 264 in the presence of styrene as a 1:1 mixture, the bicyclic compound 265 was obtained in a yield of 52%. Here, the G-I catalyst initiates an RCM process first, and subsequently promotes both inter/intramolecular Kharasch addition after heating in the presence of styrene. Overall, the ruthenium-catalyzed reactions result in the formation of four new stereogenic centers, two new carbon–halogen bonds, and three new contiguous C–C bonds within a single reaction flask.

Scheme 52 Intra- and intermolecular Kharasch addition reaction

# 8.3

Keck Radical Allylation–Metathesis

Free-radical allylation using allylstannane is a useful method for functionalizing compounds when conventional methods based on carbanion chemistry fail. Radical reactions tolerate multiple functional groups, eliminating the need for protective groups. Attempts were made to allylate the dibromo compound 266, resulting in the production of diallyl dione 267 in 76% isolated yield when the dibromide was treated with allyl(tributyl)tin in toluene at 80 °C in the presence of AIBN (Scheme [53]).[42] Subsequently, CM was utilized to obtain the cage derivative 268 in 55% yield.

Scheme 53 Application of cross-metathesis in a synthesis of cage derivative 268

#
# 9

Conjugate Addition–Metathesis

9.1

Hosomi–Sakurai Reaction–Metathesis

Scheme 54 Annulation of symmetrical triquinane derivatives by conjugate addition and RCM

Allyl(trimethyl)silane reacted with the symmetrical triquinane 269 at –20 °C in the presence of TiCl₄ as a Lewis acid, resulting in the formation of the tetraallyl product 270 in 20% yield, along with other isomers (Scheme [54]).[43] By adjusting the temperature and stoichiometry, various stereoisomers were produced, due to the creation of multiple chiral centers. An attempted RCM of tetraallyl compound 270 gave the ring-closure product 271 in 88% yield.

Scheme 55 Preparation of pentaquinane 272e by conjugate addition of allyl(triisopropyl)silane

A tetrabromo compound derived from the corresponding cage dione exists in its hydrated form 272a. Photothermal olefin metathesis of 272a under MW conditions gave the tetrabromo compound 272b in 45% yield (Scheme [55]).[43] Subsequently, this was treated with Zn/AcOH to produce the dibromo compound 272c in 49% yield along, with the byproduct 272d in 25% yield. Compound 272c reacted with allyl(triisopropyl)silane to give the (3+2) cycloaddition product 271e .

# 9.2

Robinson Annulation–Metathesis

Christmann and co-workers developed the modular strategy to generate propellane derivatives shown in Scheme [56].[44] By desymmetrizing prostereogenic ketones using a Hajos–Parrish–Eder–Sauer–Wiechert-type reaction, they established the first of two quaternary bridgehead centers. Subsequent conjugate additions to the resulting bicyclic enones 274 gave diene 275. Subsequently, by using a ruthenium catalyst, the formation of the remaining ring was completed to give the propellane derivative 275.

Scheme 56 Synthesis of a propellane derivative by a Robinson annulation and RCM

# 9.3

Petasis–Mannich Reaction–RCM

To build the fundamental core of the 2-(hydroxymethyl)dihydropyrrole unit 281 with a high enantiomeric purity and good diastereocontrol, a Petasis–Mannich (PM) condensation was used as the initial step (Scheme [57]).[45] A vinylboronic acid, an allylic amine, and TBAF were used to realize the PM condensation of 277, giving diene 280 with good diastereoselectivity (>99%) and an 83% yield. Subsequently, the 2-amino alcohol 281 was produced in 70% yield by RCM of 280 with the G-II catalyst.

Scheme 58 Synthesis of (+)-anaferine by cross-metathesis and an aza-Michael addition

Scheme 57 Synthesis of pyrrole derivatives by a Petasis–Mannich reaction and RCM

# 9.4

Cross-Metathesis–Aza-Michael Addition

By using the HG-II catalyst along with Ti(i-OPr)₄ as a co-catalyst, the sulfinyl amine 283 reacted with penta-1,4-dien-3-one (282; Scheme [58]).[46] The resulting bisenone 284 was obtained in a high yield due to the effective implementation of the bidirectional CM reaction. The feasibility of a double intramolecular aza-Michael reaction (IMAMR) was explored with the given substrate. This step was highly efficient, as it led to the formation of the bispiperidine skeleton 285, with two stereocenters being produced simultaneously. Various experiments were performed using diverse bases to identify the optimal conditions for the double cyclization. On treatment of the bispiperidine 285 with HCl in 1,4-dioxane, the sulfinyl moieties were eliminated and (+)-anaferine (286) was produced in 99% yield.

# 9.5

Oxa-Michael–Metathesis

Hydroxyalkene 288 was produced by opening the chiral epoxide 287 with 3-butenylmagnesium bromide (Scheme [59]).[47] HG-II catalyst was used to realize an oxa–Michael reaction of 288 and a subsequent CM reaction with (E)-crotonaldehyde to produce the required tetrahydropyrancarbaldehydes 289a and 289b.

Scheme 59 Synthesis of 2,6-cis/trans-tetrahydropyrancarbaldehydes

# 9.6

Aza-Michael–Metathesis

A diastereoselective tandem CM/intramolecular aza-conjugate addition reaction of acrolein with the substrate 290 using HG-II catalyst in dichloromethane at r.t. gave the corresponding tandem products 291 and 292 in 56% yield as a 3.3:1 mixture of diastereomers (Scheme [60]).[48]

Scheme 60 CM and intramolecular aza-conjugate addition reactions of acrolein

#
# 10

Multicomponent Reactions

10.1

Petasis Three-Component-Reaction–Metathesis

A combination of the Petasis three-component reaction (3-CR) and a Ru alkylidene-catalyzed RCM produced a collection of carbo-and heterocycles of various sizes. The desired olefin-containing components for the Petasis 3-CR (boronic acid, α-hydroxy aldehyde, and amine) were mixed so that the resulting amino alcohols contained two olefin functionalities aligned to undergo a Ru-catalyzed RCM and form small rings. The Petasis 3-CRs were performed in a mixture of CH₂Cl₂ and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a solvent, giving the diastereomerically pure anti-amino alcohol product 296 in 60% yield (Scheme [61]).[49] These synthetic transformations were conveniently demonstrated with a racemic α-hydroxy aldehydes masked as the corresponding lactols, e.g. 297. Substrate 298 was subjected to Ru alkylidene-catalysis. The five-membered diene 299 (87%), which was smoothly obtained in the presence of HG-II catalyst, underwent a subsequent DA reaction to produce the cycloadduct 300.

# 10.2

Ugi Four-Component Reaction–Metathesis

Complex targets can be obtained by using a Ugi four-component coupling reaction of an isocyanide, amine, aldehyde, and carboxylic acid. 2,2,2-Trifluoroethanol was used as a solvent for the reaction, and these conditions smoothly produced the (N-acylamino)amide 301 (Scheme [62]) in a good yield.[50]

Scheme 61 Petasis three-component reaction and RCM strategy

Amide 301 was then used to build the 13-membered lactam triamide 302. A diallylated metathesis precursor was produced by treating the Ugi product 301 containing two p-bromoanilide moieties with allyl iodide and Cs₂CO₃ in DMF at room temperature. This bisallylation technique can be used to produce large macrocycles. The diallyl precursor then underwent RCM at 83 °C to give product 302 in a 67% yield.

#
# 11

Miscellaneous

11.1

Babler–Dauben 1,3-Transposition–RRM

Scheme 62 Synthesis of 302 by metathesis and an Ugi four-component reaction

It was shown that readily available dicyclopentadiene (303) is an excellent precursor for RRM to produce a variety of fused polycyclic frameworks containing carbocycles (Scheme [63]).[51] In tetrahydrofuran, dicyclopentadiene was oxidized in the presence of SeO₂ under reflux conditions to produce a dicyclopentadienol. Subsequent treatment of the resulting alcohol with PCC resulted in the delivery of the tricyclic enone 304 (78% yield). The required alcohol 305 was produced in 78% yield by reaction of the enone 304 with but-3-en-1-ylmagnesium bromide. The enone 306 was then produced in 75% yield by a Babler–Dauben 1,3-transposition of the alcohol derivative 305.[51] It is important to note that the isomerization of the double bond occurred throughout a 1,3-transposition sequence, producing the conjugated enone. Treatment of the enone 306 with G-I catalyst did not produce the expected RRM product. Therefore, the G-II catalyst, which is more reactive than G-I catalyst, was used in CH₂Cl₂ with ethylene to successfully create the tricyclic enone 307 in 75% yield.

Scheme 63 Successful synthesis of tricyclic enone 307 by RRM

# 11.2

Aza-Baylis–Hillman Reaction–Metathesis

By combining a three-component sequential aza-Baylis–Hillman reaction and olefin metathesis, 2-substituted 3-(methoxycarbonyl)pyrroles, e.g. 313, were prepared (Scheme [64]).[52] The 2-(trimethylsilyl)ethanesulfonyl (SES)-protected α-methylene amino ester 311 was obtained by an aza-Baylis-Hillman reaction of SES-NH₂ (308), benzaldehyde (309), and methyl acrylate (310). Subsequent N-alkylation with allyl bromide yielded the required diene 312 under mild reaction conditions. The diene 312 was subsequently cyclized by RCM under microwave irradiation conditions with the G-II catalyst to produce the SES-protected pyrroline intermediate 313 in 98% yield.

Scheme 64 Facile synthesis of methoxycarbonyl pyrroles

# 11.3

Baylis–Hillman Reaction–Metathesis

By using a simple method, a series of enantioenriched α-substituted, α,β-unsaturated δ-lactams were prepared. For example, a Baylis–Hillman reaction of methyl acrylate (310) with acetaldehyde gave the key building block 314, which was coupled with the amino alkene 315 to give alkenamide 316 (Scheme [65]).[53] This underwent RCM with G-II catalyst to give the α,β-unsaturated δ-lactam 317 (73%). The stereochemistry at the δ-position of the lactam was determined by using Ellman’s technique.

Scheme 65 Enantioenriched α-substituted, α,β-unsaturated δ-lactams

# 11.4

N-Allylation of Cookson-Type Reagent–Metathesis

N-Substituted 1,2,4-triazoline-3,5-dione derivatives are called Cookson reagents. In this regard, dihydro Cookson’s reagents such as 318 were found to be useful substrates for constructing N-containing heterocycles. To build the highly functionalized oxygenated urazole derivatives 324 (70%) and 325 (91%), sequential N-allylation, RCM, and hydrogenation were used in a quick and effective synthetic protocol (Scheme [66]).[54]

Scheme 66 Preparation of highly functionalized urazole derivatives

# 11.5

C–H Activation–Metathesis

Compound 327 was synthesized from 2-bromo-N-allylaniline (326) in 70% yield through a palladium-catalyzed annulation with norbornadiene using the ligand t-Bu₃PHBF₄. Later, this compound was also produced by C–H activation and underwent RRM on treatment with G-I catalyst and ethylene to provide the tetracycle 328 (52% yield); the ring-opened product 329 (35% yield) was also obtained (Scheme [67]).[55]

# 11.6

Eschenmoser Fragmentation–Cross-Metathesis

Various macrocyclic ring systems were generated by using an Eschenmoser–Tanabe fragmentation, enyne metathesis, and DA reaction as key steps. Thus, epoxide 330 was treated with tosyl hydrazide in a CH₂Cl₂–AcOH mixture as the reaction medium to access the enlarged 18-membered macrocycle 331 in good yield (79%) (Scheme [68]).[56] Subsequently, macrocycle 331 reacted under cross-enyne metathesis conditions with G-II catalyst to give the diene 332 (96% yield), which proved to be an excellent precursor for a DA reaction. The exo-diene 332 was treated with tetracyanoethylene as a dienophile to generate the DA adduct 333 (96%).

Scheme 67 C–H activation and RRM to generate heterocycles.

Scheme 68 Macrocyclic ring by Eschenmoser–Tanabe fragmentation and CM

# 11.7

Fischer Indolization–Metathesis

When a FI and RCM were performed in succession, intriguing indolocarbazoles were produced, as illustrated in Scheme [69].[57] This method began with FI between cyclohexanone (334) and phenylhydrazine hydrochloride (335); periodic acid was then used for regioselective oxidation to produce 337, a suitable precursor for subsequent FI. The feasibility of the FI sequence was tested by producing the necessary substrate using the appropriate phenylhydrazine and standard reagents such as SOCl₂/EtOH, AcOH/TFA, MeCN/H₂SO₄, EtOH/H₂SO₄, and HCl. Here, a mixture of nonaromatized and aromatized compounds was obtained. However, the fully aromatized indolocarbazole 338 was obtained exclusively in 73% yield when a deep-eutectic mixture of N,N-dimethylurea (DMU) and l-(+)-tartaric acid (TA) was used. An RCM sequence was then applied to the diallyl indolocarbazole 339 with G-I catalyst in refluxing toluene, resulting in the production of macrocyclic compound 340 in 76% yield.

Scheme 69 Synthesis of indolocarbazoles by Fischer indolization and RCM

In view of our interest in the design of indole-based azapolyquinanes by employing FI and RRM as key steps, the tricyclic exo-ketone 341 was subjected to FI by reaction with phenylhydrazine hydrochloride in a low-melting mixture of TA and DMU at 90–100 °C to give the indole derivative 342 in 98% yield (Scheme [70]). The indole derivative 342 was then subjected to an N-allylation in the presence of NaH in anhydrous DMF at 0 °C to deliver the corresponding N-substituted norbornane derivative 343 in a good yield (66%). Later, the N-butenyl indole derivative 343, on treatment with G-I catalyst in anhydrous dichloromethane at r.t. for 6 h, gave the RRM product 344 exclusively in 88% yield.

Scheme 70 Synthesis of an N-substituted aza-polyquinane by RRM

To prepare spiroindole derivatives, a sequence of FI and allylation followed by an RCM reaction was used. Thus, treatment of indan-1-one (345) under FI conditions in a deep-eutectic solvent mixture of TA and DMU gave the indeno[1,2-b]indole framework 346, containing as active methylene moiety, in 98% yield (Scheme [71]). Indeno[1,2-b]indole derivative 346 was subjected to diallylation with allyl bromide using NaH as a base to furnish the diallyl compound 347 in 95% yield. Finally, compound 347 was subjected to RCM in the presence of G-I catalyst to give the ring-closure product 348 in a good yield (83%).

Scheme 71 Fischer indolization-derived spiroindole

# 11.8

Transannular Ketalization–Metathesis

When compound 349 was subjected to ketalization, the oxa-cage compound 350 was successfully obtained in 35% yield (Scheme [72]). When this tetraallyl cage derivative was subjected to RCM using G-II catalyst, the octacyclic cage compound 351 containing four-, five-, six-, and seven-membered rings in a single moiety was produced in 85% yield .[58]

Scheme 72 Synthesis of octacyclic oxa-cage 351

Scheme 73 Synthesis of oxa-cages by transannular cyclization and RCM

Kotha and co-workers conceived a new process for generating annulated oxa-cage compounds starting with Cookson’s dione and its derivatives.[58] In this regard, compound 349 was prepared by a DA reaction of cyclopentadiene with 2,5-diallylbenzo-1,4-quinone, followed by [2+2] photocycloaddition, and its structure was confirmed by ¹³C NMR spectroscopy (Scheme [73]). Next, the cage diene 352 was treated with allyl Grignard reagent to give compound 353. Subsequent O-allylation and RCM with G-II catalyst gave triene 355 (94%). Along similar lines, starting from 353, Grignard O-allylation gave 356, which on ring closure, generated 357 in 88% yield.

# 11.9

Ketalization–Metathesis

Cyclic ketal 360 was synthesized from substrate 358 in 76% yield by treatment with the chiral homoallylic alcohol 359 in the presence of 1.0 equivalent of Tf₂NH at –78 °C for one hour. In the presence of 12.5 mol% of G-I catalyst, RCM of compound 360 (76%) was accomplished easily to give the spiroketal 361 in 86% yield (Scheme [74]).[59]

# 11.10

Trimerization–Metathesis

A C ₃-symmetric triamine derivative produced by trimerization as a key step served as a crucial starting material. Compound 363 was obtained in a 72% yield through N-allylation of substrate 362 (Scheme [75]).[25] [60] Subsequently, compound 363 was subjected to a trimerization sequence with thionyl chloride (SOCl₂) in EtOH under reflux conditions to give trimer 364 in 42% yield. This trimerization sequence involves a series of aldol-type reactions. To enhance the yield of compound 364, an alternative route was chosen in which trimerization of the compound 366 and subsequent reduction of the trinitro compound 367 gave the triamine product 368 in a better yield (76%). Subsequent allylation of triamine 368 was carried out in the presence of allyl bromide and NaH in DMF at r.t. for 2 h. Substrate 364 underwent RCM and aromatization by treatment with G-I catalyst in CH₂Cl₂ at room temperature to produce the desired product 365 (83% yield).

Scheme 74 Cyclic ketal-tethered RCM strategy

Scheme 75 Synthesis of the pyrrole-containing C ₃-symmetric molecule 367

# 11.11

Cyclotrimerization–RCM

To obtain C ₃-symmetrical molecules containing a propellane unit, trimerization of compound 369 in the presence of EtOH/SiCl₄ at 0 °C to r.t. furnished the trimerized product 370 in 54% yield (Scheme [76]).[61] Next, the C ₃-symmetric product 371 was treated with allyl bromide in the presence of a 1 M solution of sodium bis(trimethylsilyl)amide (NaHMDS) in THF at –75 °C to give the RCM precursor 371 in a good yield (78%). The hexaallyl derivative 371 was then subjected to RCM using G-II catalyst (10 mol%) in CH₂Cl₂ to give the propellane-bearing C ₃-symmetric product 372 in a good yield (87%).

Scheme 76 Synthesis of a C ₃-symmetric propellane derivative by trimerization and RCM

# 11.12

Photothermal Metathesis–Microwave Irradiation Conditions

Starting with the cage dione 373, a straightforward path to triquinane frameworks, e.g., 374 and 375, under microwave irradiation conditions was investigated (Scheme [77]).[62] Due to the presence of methyl substituents on the cyclobutane rings, photothermal metathesis is possible under microwave irradiation conditions, which are milder reaction conditions than the usual flash vacuum pyrolysis conditions that require higher temperature (~600 °C) and special equipment.

Scheme 77 Straightforward path to cis-syn-cis triquinane frameworks

# 11.13

Peptide Coupling and Enyne–Metathesis

[3-(Dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (EDCl) was used to condense propargyl derivative 376 with 377 to produce a diastereomeric mixture of peptides 378 and 379 (Scheme [78]).[63] Subsequently, the synthesized tripeptide 379 was subjected to hydrolysis to generate the acid 381, which was coupled with methyl l-isoleucinate hydrochloride to furnish the alkyne-based building block 382 (95%). Enyne metathesis was then used to produce the diene 383 (76% yield), which can undergo DA reactions with suitable dienophiles.

Scheme 78 Peptide coupling and metathesis

# 11.14

Retro-Diels–Alder–Metathesis

The DA adduct 384 was allylated with allyl bromide using NaH to produce the C-allyl compound 385 in 19% yield, along with an O-allyl compound (Scheme [79]).[9] In an intriguing one-pot sequence, the diallyl compound 385 underwent both rDA and RCM reaction under metathesis conditions to produce the quinone 386 in 63% yield.

# 11.15

Weiss–Cook Condensation–FI–Metathesis

Cis-Bicyclo[3.3.0]octane-3,7-dione (386) was prepared by a Weiss–Cook reaction and then subjected to a two-fold FI to create the diindole derivative 388 (49%) under HCl/EtOH reflux conditions (Scheme [80]).[64] SeO₂ oxidation of substrate 388 in 1,4-dioxane produced the diketone 389, which on allylation by allyl bromide in the presence of NaH gave the monoallylated product 390 in 65% yield. The stereochemistry of the ring junction was preserved during the allylation reaction. The monoallyl derivative 390 underwent a second allylation with allyl bromide to yield the diallyl diketone 391 (86%). To perform RCM, compound 391 was treated with G-II catalyst in dry CH₂Cl₂ to give the required propellane derivative 392 in 94% yield.

Scheme 80 Preparation of a propellane by using a Weiss–Cook reaction, FI, and RCM

Scheme 79 rDA and the RCM reaction to produce the quinone 386

# 11.16

Garner Aldehyde– Metathesis

The naturally occurring anhydrophytosphingosine pachastrissamine, commonly known as jaspine B, has a tetrahydrofuran core and is a promising candidate for cancer treatment. Jana and Panda used the Garner aldehyde 393 as a starting material to synthesize jaspine B.[65] They employed iodocyclization, organocuprate addition, olefination, regioselective tosylation, and CM as crucial steps in their synthetic approach (Scheme [81]).

Scheme 81 Garner aldehyde and metathesis. Reaction conditions: (a) (i) vinylmagnesium bromide, THF, –78 °C, 2 h, (ii) PTSA, MeOH, 0 °C to rt, 1 h, 70% (two steps); (b) I₂/K₂CO₃, MeCN, 0 °C, 30 min, 90%; (c) 2,2-dimethoxypropane, (±)-CSA, anhyd CH₂Cl₂, 0 °C to rt, 4 h, 95%; (d) vinylmagnesium bromide/CuI/HMPA, THF, –30 °C, 1 h, 80%; (e) dodec-1-ene (A), G-II (8 mol%), anhyd CH₂Cl₂, 45 °C, 8 h, 82%; (f) H₂–Pd/C, EtOAc, 50 psi, rt, 0.5 h, 95%; (g) 6 N HCl in MeOH, 0 °C to rt, 5 h, 79%.

# 11.17

Seyferth–Gilbert Reaction–Metathesis

Williams and Smith reported a total synthesis of (+)-18-epi-latrunculol by using a CM reaction (Scheme [82]).[66] To prepare the key precursor 401, allylation and a CM reaction were employed. The GH-II catalyst was helpful in coupling the homoallylic alcohol and enone to provide the cyclization precursor 401 in 70% overall yield. Selective oxidation of the diol 402 followed by alkyne formation and TBS protection delivered the crystalline alkyne 403 in 54% yield. A subsequent Mitsunobu macrolactonization led to an enantioselective total synthesis of the cytotoxic latrunculin congener (+)-18-epi-latrunculol (404).

Scheme 82 Enantioselective synthesis of cytotoxic (+)-18-epi-latrunculol; (–)-ipc₂BOMe = B-methoxydi(isopinocampheyl)borane

# 11.18

Rongalite–Metathesis

The open-chain alkene-terminated sulfones 406 were obtained by treatment of the corresponding alkenyl bromides with rongalite (sodium hydroxymethylsulfinate) (Scheme [83]).[67] The reaction was performed at room temperature with potassium carbonate as a base in the presence of tetrabutylammonium bromide (TBAB). The symmetric bisoleﬁnic sulfones 406 were then subjected to an RCM protocol to aﬀord the cyclic sulfones 407.

Scheme 83 Synthesis of sulfones using RCM

#
# 12

Conclusions

Here, we have included many interesting examples involving a metathesis sequence combined with other named or unnamed reactions. It is interesting to assemble complex molecules utilizing metathesis as a key step, as these targets are not easy to assemble without the use of a metathesis step. The metathesis route has provided a new retrosynthetic strategy toward several target molecules and for C–C bond formation. All the known examples in this regard cannot be included here due to space constraints, and we take responsibility for our selection. We hope that our review will catalyze further thinking in this direction.

#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgements

N.K.G., S.A., and D.S. thank IIT Bombay for providing facilities and an IPDF fellowship. We thank our co-workers who contributed to our research in this area. Their names are included in the form of references in reference section.

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Corresponding Author

Sambasivarao Kotha

Department of Chemistry, Sunandan Divaita School of Science, (SVKM’S NMIMS) (Deemed-to-be) University

Vile-Parle, Mumbai, Maharashtra, 400056

India

Email: sambasivarao.kotha@nmims.edu

Publication History

Received: 07 July 2024

Accepted after revision: 05 August 2024

Accepted Manuscript online:
05 August 2024

Article published online:
10 September 2024

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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