Modular Approaches to Cyclopentanoids and their Heteroanalogs

Abstract

Cyclopentanoids and their derivatives are interesting targets in synthetic organic chemistry due to their extensive applications in various branches of chemical sciences like pharmaceuticals, natural and non-natural products. In view of these applications, several synthetic strategies have been developed in the past three to four decades. In this article, we describe our work towards the synthesis of cyclopentanoids and their heteroanalogs involving diverse synthetic strategies during the past two decades. Among these, photo-thermal olefin metathesis, ring-closing metathesis, ring-rearrangement metathesis, cyclopentane annulation, [2+2+2] cycloaddition and Diels–Alder reactions have been used to assemble cyclopentane rings of diverse architecture.

1 Introduction

2 Synthesis of Spiro[4.4]nonane (A1) Derivatives

3 Synthesis of Octahydropentalene (A2) Derivatives

4 Synthesis of Linear Triquinanes (A3)

5 Synthesis Spiro Triquinanes (A4)

6 Synthesis of Angular Triquinane (A5) Systems

7 Synthesis of Hexahydro-2′H-spiro[cyclopentane-1,1′-pentalene] (A6) Ring System

8 Synthesis of Dispiro[4.1.47.25]tridecane (A7) Ring System

9 Synthesis of Hexahydro-1H-3a,7a-propanoindene Ring System

10 Synthesis of Linear Tetraquinanes (A11 and A12)

11 Synthesis of Tetrahydro-1′H,3′H-dispiro[cyclopentane-1,2′-pentalene-5′,1′′-cyclopentane] (A13) Ring System

12 Synthesis of Decahydro-1H,8H-dicyclopenta[a,h]pentalene (A14) Ring System

13 Synthesis of Dodecahydro-1H-dicyclopenta[a,d]pentalene (A15) Ring System

14 Synthesis of Octahydro-1′H-spiro[cyclopentane-1,2′-cyclopenta[c]pentalene] (A16) Ring System

15 Synthesis of Decahydrospiro[cyclopentane-1,7′-cyclopenta-[a]pentalene] (A17) Ring System

16 Synthesis of Compact Tetraquinane (A18)

17 Synthesis of Higher Polyquinanes

18 Conclusions

19 Acronyms

Key words

cyclopentanoids - metathesis - cycloaddition - allylation - Grignard reaction - Fischer indolization - Claisen rearrangement

Biographical Sketches

Prof. Sambasivarao Kotha received his M. Sc. degree in Chemistry from the University of Hyderabad (UoH) and then obtained a Ph.D. in Organic Chemistry from UoH in 1985. He continued his research at the UoH 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. In 2001, he was promoted to Professor. He has published 295 publications in peer-reviewed journals and was elected as a fellow of various academies (FNASc, FASc, FRSC, and FNA). He was also associated with the editorial advisory board of several journals. His research interests include organic synthesis, green chemistry, unusual amino acids, peptide modification, cross-coupling reactions, and metathesis. Currently, he occupies the Pramod Chaudhari Chair Professor in Green Chemistry (Praj Industries).

Dr. Yellaiah Tangella was born in Telangana, India. He obtained the master degree in Organic Chemistry from SR&BGNR College, Kakatiya University and received his Ph.D (2019) in chemical sciences from CSIR-­Indian Institute of Chemical Technology, Hyderabad under the supervision of Dr. Bathini ­Nagendra Babu and co-supervision of Dr. Ahmed Kamal. He is currently a postdoctoral researcher under the guidance of Prof. S. Kotha at Department of Chemistry, Indian Institute of Technology Bombay, and Mumbai, India. His research interests include the development of novel strategies to access diverse medicinally interesting heterocycles.

1

Introduction

Polyquinanes consist of fused cyclic compounds containing three or more cyclopentane rings. Cyclopentanoids are considered as privileged structures, present in numerous natural (Figures [1–3], N1–N101) and non-natural products (Figure [4]), and they are core structures of several drug-related molecules. After the structure elucidation of the first cyclopentanoid natural product, i.e., hirsutic acid C (Figure [2], N54) in 1966, several cyclopentanoid natural products were isolated from a wide range of plant, microbial, and marine sources. Since then, synthesis of natural and non-natural products containing cyclopentane rings has become a vibrant area of chemical research. Hirsutic acid C is a linearly fused triquinane based sesquiterpene with potent antibiotic and antitumor properties, isolated from basidiomycetes Stereum hirsutum in 1946.[1] Similarly, coriolin (Figure [2], N55) is a linear triquinane with eight asymmetric centers, that displays prominent antibacterial and antitumor activities,[2] hirsutene (Figure [2], N56) is a known fungal metabolite isolated from basidomycete Coriolus consors,[3] and cucumins A–C (Figure [2], N57–N59) were isolated from mycelial cultures of the agaric Macrocystidia cucumis and found to display promising antimicrobial and antitumor activities.[4] Subergorgic acid (Figure [2], N71) is an angularly fused triquinane with cardiotoxic activity, isolated from the Pacific gorgonian coral Subergorgia subeross [5] and its derivatives act as a promising antifouling agents.[6] Likewise, retigeranic acid (Figure [2], N83 and N84) is an angularly fused sesterterpenoid that exhibits a wide range of pharmacological properties.[7]

Presilphiperfolanol belongs to cyclohexane fused diquinane sesquiterpenes with modest biological activity. In this category, presilphiperfolan-8α-ol (Figure [1], N8) was the first member to be isolated from Eriophyllum staechadifolium and Flourensia heterolepis.[8] The later presilphiperfolan-9α-ol (Figure [1], N9) was isolated from Artemisia lacinata and Artemisia chamaemelifolia, which possesses toxicity to the peripheral and central nervous system of insects as well as antifeedant properties, and application as a fragrance compound.[9] Finally, presilphiperfolan-1β-ol (Figure [1], N10), which was isolated from the fern Anemia tomentosa var. anthriscifolia and characterized, exhibits potent antimycobacterial properties.[10] Crinipellin A (Figure [3], N89) contains angularly and fused linear triquinane hybrid tetraquinane and was found to exhibit potent antibiotic activity; it was first isolated from the strain of basidiomycetes fungus Crinipellis stipitaria (Agaricales).[11]

Figure 1 Medicinally interesting natural products containing at least two five membered rings.

Spiro compounds are prevalent structures in medicinal chemistry due to their occurrence in nature; they exhibit intrinsic complexity, conformational rigidity, and their structural features display several biological properties and impressive applications in various fields.[12] Among spiro compounds, fredericamycin A (Figure [1], N48) is a well-known antibiotic and antitumor agent, isolated from a strain of Streptomyces griseus, which contains a hexacyclic ring system featuring two spiro cyclopentane rings.[13] Interestingly, indane and its derivatives are important structural motifs found in a large number of medicinally useful natural products and therapeutic agents.[14] For example, pallidol (Figure [1], N49) is a dimer of resveratrol, initially isolated form Cusses pallida and later from red wine, and it shows strong antioxidant and antifungal activities.[15] Furthermore, some of these compounds are useful as catalysts and chiral ligands with significant applications in organic syntheses and also suitable in designing numerous metallocene complexes.[16]

Cyclopentane fused with arenes and hetero-arenes are also interesting targets in drug discovery programs due to their presence as core units in several bioactive natural products and pharmaceuticals. For instance, roseophilin (Figure [1], N53) is a cyclopentane fused pyrrole macrocycle with significant antibiotic and anticancer properties that was isolated from Streptomyces griseoviridis.[17] Nakadomarin A (Figure [1], N47) is a cyclopentannulated furan alkaloid with potential antimicrobial and cyclin-dependent kinase 4 inhibitory activities.[18] Among the hetero-quinanes, the cyclopenta[b]indole core is a good scaffold due to its occurrence in a large number of natural products with diverse biological activities, medicinally important compounds and drugs.[19] For example, Fischerindole L (Figure [1], N50), which shows good cytotoxic activity against lung cancer cell line HCl-H460, was isolated from Fischerella muscicola.[20] Yuehchukene (Figure [1], N31) is a cyclopentannulated bis-indole scaffold, isolated from Murraya paniculata, that possesses estrogenic and anti-fertility activities.[21] Spiroindimicins B–D (Figure [2], N86-N88) feature spiro bis-indole frameworks with moderate cytotoxicity against several cancer cell lines.[22] Other biologically interesting natural products bearing fused/spiro cyclopentane ring systems like ramipril (Figure [1], N2), paxilline (Figure [1], N18), (–)-agelastatin A (Figure [1], N3), variecolol (Figure [1], N16) and spiroapplanatumine K (Figure [1], N22) and some other natural products are shown in Figures [1–3].[23]

In addition, cyclopentannulated thiophenes and benzothiophenes are an interesting class of heterocycles because of their significant applications in pharmaceutical chemistry and materials science.[24`] [b] [c] Hence, several synthetic approaches have been explored towards the preparation of these privileged structural motifs involving classical and transition-metal mediated approaches. However, as a part of our major research program, we have developed diverse synthetic strategies to various polyquinanes using cycloaddition reactions [e.g., (2+2), (4+2) (Diels–Alder (DA) reaction),[24d,e] retro-Diels–Alder reaction[24f] and (2+2+2)], Claisen rearrangement (CR),[24g] ring-closing metathesis (RCM),[24h] [i] ring-opening metathesis (ROM), ring-rearrangement metathesis (RRM),[24j] ring-opening cross-metathesis (ROCM),[24k] ring-closing enyne metathesis (RCEM),[24l] enyne ring-rearrangement metathesis (ERRM), photo-thermal olefin metathesis and Fischer indolization (FI)[24m] as key steps.

Figure 2 Medicinally interesting natural products containing three cyclopentane rings

Figure 3 Medicinally interesting natural products containing four five-membered rings

There are several theoretically interesting molecules (Figure [4]) such as dodecahedrane (T1), pagodane (T2), trishomocubane (T3), [5]prismane (T4), [4]peristylane (T5), and [4.5]coronane (T6) and trinorbonane (T7), which contain fused five-membered rings. Heptacyclotetradecane (T8) contains a heptacyclic system, which is considered a rich repository of five-membered rings.[25a] [b]

Figure 4 Theoretically important molecules containing five-membered rings

Even though several reviews have been reported,[7c] to our knowledge none of these reviews cover the synthetic approaches that deal with a broad range of polyquinanes that are described here. The current review includes a detailed account of various synthetic transformations developed in our group over the last few decades. Here, we covered the synthesis of a variety of linear, angular, fused, and spiro polyquinane derivatives and their hetero analogs from our work. We have shown all major possible arrangements of various cyclopentanoids up to four five-membered rings (Figure [5]). For example, when two five-membered rings are involved, two possible arrangements are shown in Figure [5](i). Similarly, in case of three five-membered rings, eight possible arrangements are shown in Figure [5](ii). Figure [5](iii) shows some of the possible arrangements of four five membered rings. We did not show all the possible stereochemical arrangements at the ring junction. During our discussion we have mentioned most of the synthetic schemes that we reported from our group. By no means does Figure [5] contain all the possible arrangements. However, most of the major possible arrangements are included.

2

Synthesis of Spiro[4.4]nonane (A1) Derivatives

Figure 5 Possible assemblies of cyclopentanoids containing two, three, and four cyclopentane rings

Spirocyclic [4.4] scaffolds containing a carbo framework or heteroatom containing unit are widely represented in natural products. Figure [6] demonstrates the variety of [4.4] spirocyclic scaffolds present in diverse natural product domains.[25c] Several such combinations were prepared in our study. In 1999, our group reported an efficient two-step method for the synthesis of spiro derivatives in good to excellent yields from commercially available compounds containing a β-diketone moiety such as 1 through metathesis. Initially, we prepared the RCM precursor 2 through a Pd-catalyzed diallylation of 1,3-carbonyl compounds 1. Later on, treatment of diallyl dione 2 with a catalytic amount of ruthenium catalyst generated the spiro derivatives 3 in good yields (Scheme [1]).[25d] [e]

Figure 6 Diverse [4.4.0] spirocyclic scaffolds present in the natural products

Scheme 1 Synthesis of spiro derivatives 3a–c by RCM

In 2015, we reported an efficient strategy to generate diverse spirocycles through a [2+2+2] cycloaddition and DA reaction sequence starting with readily available substrates. We begin our journey with the propargylation of active methylene compounds (AMCs) such as 4 containing carbonyl or β-dicarbonyl functionality with propargyl bromide (5) under basic conditions to generate the dipropargyl derivative 6 (Scheme [2]). The cycloaddition sequence of 6 with 2-butyne-1,4-diol (7) in the presence of a catalytic amount of Wilkinson’s catalyst [Rh(PPh₃)₃Cl] and titanium isopropoxide [Ti(OⁱPr)₄] provides the spiro diol 8, which was further utilized in the next step without any purification. These diols were converted into the dibromo compounds 9 by treating with PBr₃. The dibromo compounds on reaction with rongalite produced spiro-sultine derivatives 10 in good yields. Further, treatment of sultines with various dienophiles 11 generated the corresponding cycloadducts through a DA sequence, which was aromatized using DDQ to give 12. Aromatic bromo derivatives are useful substrates to generate a library of new compounds using the cross-coupling reactions (Scheme [2]).[26]

Recently, we demonstrated an efficient synthetic protocol for the construction of the ABCD ring fragment of the natural product, fredericamycin A (Figure [1], N48), from commercially available inexpensive starting materials utilizing CR, DA reaction and RCM as key steps. To this end, we started our journey with a known indanone derivative 13 (Scheme [3]). Later, the key RCM precursor 15 was prepared by the treatment of the indanone 13 with allyl bromide (14) in the presence of sodium hydride (NaH). Then, the RCM of diallyl compound 15 with Grubbs’ second-generation (G-II) catalyst furnished the desired BCD ring system 16 of the fredericamycin A in 89% yield. Finally, sequential transformations consisting of oxidation, DA reaction, CR and RCM generated the ABCD fragment 17 of the fredericamycin A, involving seven steps (Scheme [3]).[27]

Carbon-rich polycyclic aromatic hydrocarbons (PAHs) have been attracting a great deal of interest due to their unique photophysical properties. We envisioned a new approach to truxene 18 and spirotruxene such as 21, as important building blocks for the preparation of aromatic dendrimers. The truxene 18 was prepared by acid-mediated cyclotrimerization of 1-indanone in 70% yield. Nitration of 18 followed by allylation at three active methylene sites provided the corresponding hexaallyl precursor 20, which undergoes G-II catalyzed metathesis to generate the spirotruxene 21 in 80% yield (Scheme [4]). This strategy has also been extended to synthesize spirofluorene derivatives in good yield.[28]

Kotha and Ali reported a diversity-oriented approach to spiro diquinanes bearing α-amino acids (AAAs), and sulfones starting from easily accessible AMCs. Treatment of AMCs 22 with tetrabromo derivative 23 in the presence of potassium carbonate (K₂CO₃) gave the key precursor spiro dibromo derivatives 24 (Scheme [5]). Later, K₂CO₃ mediated alkylation reaction of dibromo compound 24 with diethyl acetamidomalonate (DEAM) furnished the spiro 1,2,3,4-tetrahydroisoquionline-3-carboxylic acid (Tic) derivatives 25 in good yields. Likewise, the same reaction with ethyl isocyanoacetate (EICA)[29a] instead of DEAM followed by hydrolysis with conc. HCl/EtOH provided the corresponding constrained AAA derivatives 26.[29b] [c] Afterwards, treatment of compound 24 with EICA followed by hydrolysis and acetylation with acetic anhydride led to the formation of spiro N-acetyl AAA derivative 27 in 66% yield. Finally, the dibromo building blocks 24 were treated with rongalite to generate the sultine derivatives, which then rearranged to the spirosulfones 28 in good yields under thermal conditions (Scheme [5]).[29d]

Scheme 2 Synthesis of diverse spirocycles containing two five-membered rings

Scheme 3 Synthesis of the ABCD ring system of fredericamycin A (N48)

Scheme 4 Synthesis of spirotruxene 21

Scheme 5 A diversity-oriented approach to spiro aromatic compounds. Reagents and conditions: i. DEAM, K₂CO₃, TBAHS, MeCN, rt, 15–20 h, 37–69%; ii. (a) EICA, K₂CO₃, TBAHS, MeCN, rt, 14–17 h; (b) HCl/EtOH, rt, 1–2 h, 45–59%; iii. (a) EICA, K₂CO₃, TBAHS, MeCN, rt, 14–17 h; (b) acetic anhydride (Ac₂O), MeCN, 30 h, 66%; iv. (a) rongalite, TBAB, DMF, 0 °C–rt, 3–6 h, 64–92%, (b) PhMe, reflux, 10–15 h 76–91%.

We have successfully demonstrated the RCEM and DA strategy for the synthesis of indan-based spiroquinanes in good to moderate yields. A selective monopropargylation of indan-1,3-dione (29) with propargyl bromide (5) was accomplished with 10% KOH and catalytic amounts of copper powder (Scheme [6]). Subsequently, allylation of 30 was realized under the phase-transfer catalysis (PTC) conditions to provide the corresponding RCEM precursor 31. The RCEM of 31 gave the desired diene 32 in the presence of G-II catalyst and a catalytic amount of Ti(OiPr)₄. Finally, the DA cy­cloaddition of diene 32 with a variety of dienophiles (11) followed by MnO₂ aided aromatization yielding the corresponding indan-based spiro derivatives 33 (Scheme [6]). Subsequently, the key intermediate indane-based diene 34 was obtained from the commercially available indan-1,3-dione (29) through a multi-step synthetic sequence. The diene 34 was treated with diverse alkyne partners 11 followed by the DDQ oxidation to deliver the corresponding spiro-indane derivatives 35 in good yields (Scheme [7]). This strategy produced a library of interesting spiro-indanes 35a–d.[30]

Scheme 6 Synthesis of angularly fused bis-indane derivatives

In addition, we also constructed the indan-based spiro compounds in good to moderate yields by utilizing the [4+2] and [2+2+2] cycloaddition strategies. To this end, we synthesized two key intermediates 37 and 38 through the alkylation of indan-1,3-dione (29) under PTC conditions with propargyl bromide (5) and 2,3-bis(iodomethyl)buta-1,3-diene (36) respectively (Scheme [8]). The [2+2+2] cy­cloaddition of 37 with various acetylene derivatives 11 furnished the corresponding spiro derivatives. Similarly, DA reaction of 38 provides intricate spiro compounds containing quinone moiety in good yields (Scheme [8]). Higher yields were obtained in [4+2] cycloaddition than [2+2+2] cycloadditions.[31]

Scheme 7 Synthesis of spiro-indane derivatives by DA approach

Scheme 8 Spiroindane derivatives through [4+2] cycloaddition strategy

We have successfully assembled complex spiroindane derivatives 46 by employing the DA cycloaddition and ROCM as key steps. For this purpose, cyclopentadiene (41) was treated with 1,2-bis(bromomethyl)benzene (40) in the presence of potassium hydroxide (KOH) under the PTC conditions to generate the sprirodiene 42, which, upon DA cy­cloaddition with quinone derivatives 43, provided the corresponding DA adducts 44. Finally, spiroindane derivatives 46 were produced in good yields by the ROCM with G-II catalyst form DA adducts 44 and 1,4-diacetoxybut-2-ene 45 (Scheme [9]).[32]

The synthesis of norbornene fused spiro diquinane 49 was realized starting with the key precursor endo-dicyclopentadiene-1-one (47), which was obtained from the commercially available dicyclopentadiene based on the known protocol. Reduction of 47 with Zn-AcOH followed by the allylation with allyl bromide (14) in the presence of NaH gave the diallyl compound 48. Later, the diallyl derivative 48 was treated with G-II catalyst to produce the corresponding unsaturated spiro diquinane 49 in 82% yield (Scheme [10]). Spiro norbornene 49 was further utilized to assemble a library of quinane derivatives by allylation/metathesis sequence.[33]

Scheme 9 Synthesis of complex spiroindane derivatives by cross-metathesis (CM)

Scheme 10 Synthesis of norbornene fused spiro diquinane

It is worth mentioning that the alkylation reaction between indan-1,3-dione (29) and tetra-bromo compound 23 in the presence of a base led to the formation of the dibromo spiro-oxepine 51 (39%) along with the spiro dimer 50 (14%) through an unusual rearrangement (Scheme [11]). The compound 51 was treated with the rongalite (Na⁺HOCH₂SO₂ ⁻), followed by the DA reaction with naphthoquinone (43) to produce the corresponding DA adduct 52 in good yield. The spiro compound 53 was generated by rearrangement followed by aromatization using the MnO₂ (Scheme [11]).[34]

Scheme 11 Synthesis of spiro derivatives by cyclization strategy

A simple approach to diverse spirofluorenes from easily accessible starting materials through RCM and SM cross-coupling reactions has been reported. The synthesis began with the generation of dibromofluorene 55, prepared by the acid-mediated bromination of fluorene 54 (Scheme [12]). Further, treatment of compound 55 with an excess amount of allyl bromide (14) in the presence of tetrabutylammonium bromide (TBAB) under basic conditions gave the diallyl compound 56. RCM of diallyl derivative 56 with the aid of Grubbs’ first-generation (G-I) catalyst yielded the dibromo substituted spirofluorene 57. The SM reaction of compound 57 with commercially available aryl/heteroaryl boronic acids 58 in the presence of Pd(PPh₃)₄ and sodium carbonate (Na₂CO₃) resulted a library of new spirofluorene derivatives 59 in good to excellent yields (Scheme [12]).[35]

Scheme 12 Synthesis of diverse spirofluorene derivatives by RCM

Along similar lines, we accomplished the assembly of spirocyclic indanone derivatives through a RCM sequence. The spiro-indanones were successfully accessed by a two-step protocol starting with 2,3-dihydro-1H-inden-1-one (60), which was treated with allyl bromide (14) in the presence of NaH to obtain the diallyl indanones 61 (Scheme [13]). The RCM sequence of diallyl indanones 61 with the aid of G-I catalyst gave the corresponding spiro-indanones 62a–d in good yields. Further, a library of new spiro compounds 63a–d have been prepared in good to excellent yields through a SM cross-coupling of bromo-spirocycle 62c with diverse arylboronic acids 58 using Pd catalyst (Scheme [13]).[36]

Scheme 13 Synthesis of spiro-indanone derivatives by RCM

Rhodanines and thiazolidinediones are five-membered heterocycles that are privileged structures in medicinal chemistry due to their inherent hydrophobic interactions, hydrogen bonding, and metal ionic interactions at the ligand binding site of proteins. In view of the interesting biological and pharmacological properties of rhodanines, we have investigated a new route for the preparation of spiro-rhodanine/thiazolidinedione derivatives through molybdenum catalyzed [2+2+2] cyclotrimerization sequence. The substituted rhodanines/thiazolidinediones 64 (x = S/O; Scheme [14]) were synthesized using inexpensive starting materials by known chemical transformations. Treatment of compound 64 with propargyl bromide (5) in the presence of K₂CO₃ delivered the dipropargyl synthons 65. A metal-mediated [2+2+2] cyclotrimerization of compounds 65 with substituted alkyne partners 11 under the microwave irradiation (MWI) conditions provided the corresponding halo substituted spiro-rhodanines/thiazolidinediones 66. Furthermore, benzene ring fused spiro-rhodanine 67 was successfully synthesized by the reaction of N-tert-butyl substituted rhodanine 64 with 1,2-bis(bromomethyl)benzene (40) in the presence of K₂CO₃. In addition, some of these compounds have been utilized to generate a library of new rhodanines/thiazolidinediones through a sequence of established chemical transformations (Scheme [14]).[37]

Scheme 14 Synthesis of spiro-rhodanines/thiazolidinediones by a [2+2+2] cycloaddition strategy

Spirooxindole and its derivatives are found in numerous natural products, and medicinally interesting molecules such as spirotryprostatin A, elacomine, horsfiline, antibacterial agent and antimalarial drug NITD609.[38] There is thus a need for the development of novel approaches to their syntheses. In this regard, we have disclosed a facile route to functionalized spirooxindole derivatives via the DA reaction. Bromination of durene (68) with N-bromosuccinimide (69) under photochemical conditions gave the tetrabromo derivative 23, which, on treatment with N-protected oxindoles (70), gave the corresponding dibromo spirooxindoles 71 (Scheme [15]). An isomeric mixture of sultine derivatives 72 and 73 was obtained by treating the oxindoles 70 with rongalite in the presence of TBAB. The sultine derivatives 72 and 73 obtained were subjected to a DA reaction with various dienophiles (11) to yield diverse spirooxindole derivatives 74a–g. In addition, we synthesized sulfones containing spirooxindole 75 through the rearrangement of a mixture of sultine derivatives 72 and 73 under thermal conditions (Scheme [15]).[39]

Scheme 15 A concise approach to spirooxindole by a cyclization strategy

We explored a simple [2+2+2] cyclotrimerization approach to the spiro hydantoins using easily accessible starting material 76 (Scheme [16]). The propargylation reaction was carried out in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) to generate the di-propargyl hydantoin 77, which underwent a molybdenum catalyzed cyclotrimerization with various acetylenes 11 to afford the corresponding spiro hydantoins 78a–d in good yields (Scheme [16]).[40]

Scheme 16 Synthesis of spiro hydantoins by a [2+2+2] cycloaddition strategy

Spirolactones are attractive targets due to their occurrence in several natural products and medicinally and pharmaceutically important targets. Our group successfully reported a practical approach for the preparation of 3,8-dimethyl-2,7-dioxaspiro[4.4]nonane-1,6-dione (81) in good yield. The diastereomeric mixture of spirolactones 81a–c were obtained by the diallylation of ethyl malonate (79) followed by the acid-mediated hydrolysis and subsequent cyclization. The structures of diastereomers 81a–c were confirmed by the NMR spectral data and further supported by the X-ray diffraction studies (Scheme [17]).[41]

Scheme 17 Synthesis of spirolactones by acid-catalyzed cyclization

Spiro diquinanes 85 have been assembled by our group from 1,3-dicarbonyl compounds such as tetronic acid (82a) and thiotetronic acid (82b) by utilizing CR and RCM strategy. Allylation of acids 82 with allyl bromide (14) in the presence of a base furnished a mixture of allyl derivatives 83 and 84. Later, the undesired O-allyl derivatives 83 were converted into the desired RCM precursors 84 by CR. Finally, the spiro compounds 85 were obtained in good yields by the RCM of diallyl precursor 84 with the aid of G-I catalyst (Scheme [18]).[42]

Scheme 18 Synthesis of spiro diquinanes containing hetero atom by RCM strategy

Pyrazoles are ubiquitous in numerous bioactive natural products, drug-related molecules and agrochemicals.[43] Hence the development of new methods to access these novel heterocycles is a useful exercise to organic chemists. Herein, we applied the same strategy for the construction of spiro-pyrazole derivatives. Allylation of phenyl substituted pyrazole 86 with allyl bromide (14) in the presence of benzyltriethylammonium chloride (BTEAC) gave the diallyl pyrazole 87, which, upon treatment with G-I catalyst, gave the corresponding spiro-pyrazole 88 through the RCM sequence (Scheme [19]).[44]

Scheme 19 Synthesis of spiro-pyrazole by RCM

3

Synthesis of Octahydropentalene (A2) ­Derivatives

In view of the importance of fused cyclopentanoids in natural and non-natural products synthesis, a new approach for the preparation of linear diquinanes starting with endo-enone 47 was investigated (Scheme [20]). The saturated dimethyl compound 89 was generated by reduction followed by the methylation of key intermediate 47. The allylation of compound 89 with allyl bromide (14) in the presence of potassium hydride (KH) provided the monoallyl compound 90, which was then subjected to RRM with G-II catalyst under ethylene atmosphere. Unfortunately, we obtained the diquinane 91 through ROM instead of the expected triquinane via RRM (Scheme [20]).[45]

Scheme 20 Synthesis of linear diquinane by ROM

Recently, our group described a new approach to diquinane 94 containing a cyclopropane moiety from a key intermediate 92, which was obtained by the reaction of 47 with sulfur ylide.[45] Allylation of the keto compound 92 followed by metathesis with G-I catalyst provides the cyclopropanated diquinane 94. Additionally, the same diquinane 94 was also synthesized from compound 92 through the ROM process of 92 followed by the allylation sequence of compound 95 (Scheme [21]).[33]

Scheme 21 Synthesis of linear diquinane containing cyclopropane by a ROM strategy

Kotha et al. reported a new approach to the construction of monoalkyl derivatives of cis-bicyclo[3.3.0]octane derivative 100 using alkyl halides (Scheme [22]). Initially, several reaction conditions were attempted to synthesize monoalkyl derivatives of cis-bicyclo[3.3.0]octane-3,7-dione, but unfortunately all met with little success. The bicyclic derivative 98 has been obtained by performing the Weiss–Cook reaction between t-butyl ester of ketoglutarate 96 and glyoxal 97. The bis-enol ether 99 was prepared by treating the tetra ester 98 with diazomethane. The monoalkyl diones 101 were prepared by KH mediated alkylation with different alkyl halides at low temperature followed by the acid hydrolysis and decarboxylation. By applying this strategy, various monoalkyl cis-bicyclo[3.3.0]octane-3,7-diones 101 have been synthesized in 78−93% yield (Scheme [22]).[46]

Scheme 22 Synthesis of diverse monoalkyl diquinanes by Weiss–Cook reaction

In connection with polyquinanes syntheses, an advanced protocol has been developed to prepare diallyl cis-bicyclo[3.3.0]octane-3,7-diones 104 and 105 via the Weiss–Cook reaction involving two paths as shown in Scheme [23]. Reaction of tetra ester 99 with allyl bromide (14) in the presence of a base followed by subsequent hydrolysis provided the corresponding diallyl diones 104 and 105. Preparation of 99 involves the use of diazomethane, which is not desirable on a large scale. Alternatively, an efficient route involved the construction of an important dione 102 via the Weiss–Cook reaction followed by hydrolysis of glyoxal and β-ketoglutarate. Dione 102 is a key building block to generate various fused cyclopentanoids. CR route involving the dione 102 and allyl alcohol (103) in the presence of PTSA provided diallyl diones 104 and 105 in 50% and 32% yields, respectively (Scheme [23]).[47]

Scheme 23 Synthesis of allyl diquinanes via CR

In another occasion, our group has performed studies for the building of another natural product core, namely tricycloclavulone, which contains a linear diquinane derivative fused with spirocyclobutanone.[48] To this end, compound 107 was prepared by Zn/AcOH mediated dechlorination of 106. Further, synthesis of triallyl derivative 108 was achieved by the reaction of 107 with allyl bromide, which then undergoes ROM and RCM with the aid of G-I catalyst to provide the fused diquinane 109 in good yield. Likewise, diquinanes 112 and 114 were constructed in good yields via ROM of compound 111 and RRM-RCM of compound 113, respectively (Scheme [24]).[49]

Scheme 24 Synthesis of cyclobutane fused linear diquinane by ROM

Recently, we established a new route to substituted diquinanes form tetracyclic precursor 115, obtained from the commercially available starting materials. To generate the target quinanes, initially, compound 115 was treated with allyl bromide (14) in the presence of NaH to obtain the O-allyl compound 116. RRM of the latter with the aid of G-II catalyst delivered the corresponding pyran fused diquinane 117 in 75% yield. Afterward, metathesis of the tetracyclic compound 115 with G-II catalyst generated the tetravinyl diquinane 118 in good yields through ROM process (Scheme [25]).[49]

Scheme 25 Facile approaches to substituted linear diquinanes by metathesis

Propellanes are a unique class of compounds that are present as core structural units in a variety of bioactive natural products. In this regard, we reported a new synthetic strategy to indane-based propellanes by using RCM as a key step (Scheme [26]). The key indane-dione (121) was prepared from commercially available ethyl phenylacetate (119). Condensation of 119 followed by intramolecular cyclization gave the dione 121. The latter was converted into monoallyl indane derivative 122 by reacting with allyl bromide (14) in the presence of NaH. This allyl dione 122, on reaction with alkyl bromides, gave 123, which undergo RCM to produce 124. Compounds 124 were hydrogenated to provide the corresponding propellane derivatives 125 (Scheme [26]).[50]

Scheme 26 Synthesis of propellane bearing linear diquinane derivatives involving RCM

A diversity-oriented approach has been investigated for the construction of several linear diquinanes in good yields using a simple building block such as dicyclopentadiene. The key precursor 126 was prepared by SeO₂ oxidation of dicyclopentadiene under reflux conditions (Scheme [27]).[51] Treatment of the compound 126 with allyl bromide (14) in the presence of NaH generated the O-allyl compound 127, which, upon RRM with G-I catalyst, yielded the resulting diquinane bearing oxacycle 128 in 78% yield. Subsequently, O-propargylation of compound 126 followed by the RRM provided the corresponding diene 130, which, on treatment with different types of dienophiles (11) under the DA reaction conditions, generated the annulated diquinane 131 bearing oxacycle (Scheme [27]).[51]

Scheme 27 A diversity oriented approach to polycycles bearing linear diquinanes by RRM

The cyclic ether moiety is widespread in a number of bioactive natural products like isosorbide, inostamycins and polyether antibiotics, and some of these derivatives exhibit significant biological activity.[52] FDA-approved therapeutic drugs like idarubicin (antitumor antibiotics) and floxuridine (antimetabolite) contain a cyclic ether linkage and it is evident that these are interesting structural motifs for the discovery of useful drugs. Hence, we developed a new protocol to assemble spirocyclic ether 136 using dione 132 via a Grignard addition and RCM as key steps (Scheme [28]). The dione 132 was obtained in good yield from an easily accessible 1,5-cyclooctadine through a three-step sequence.[53] The Grignard addition between dione 132 and allylmagnesium bromide (133) provided the diallyl diol 134, which, on treatment with allyl bromide (14), gave the RCM precursor 135. Finally, the tetra allyl compound 135 was subjected to the metathesis with the aid of G-I catalyst to generate the pyrano-spirocyclic ether 136 in excellent yield (Scheme [28]).[54]

Scheme 28 Synthesis of pyrano-spirocycle by RCM

Subsequently, the same sequence of steps has been applied to the construction of other spirocyclic ethers 139a and 139b and propellane containing pyrano spirocyclic ether 139c in good yields starting with substituted cis-bicyclo[3.3.0]octane-3,7-diones 102 (Scheme [29]).[54] [55]

Scheme 29 Synthesis of linear diquinane containing pyrano-spirocyclic ether

We have reported a simple synthetic protocol to produce oxa-bowls starting with the tricyclic enone 140, which was prepared by following known procedures.[51] Reduction of the ketone 140 with diisobutylaluminum hydride (DIBAL-H, 141) and subsequent allylation with allyl bromide (14) under basic conditions generated O-allyl tricyclic compound 143 (Scheme [30]). Later, O-allyl compound 143 was subjected to RRM with the aid of G-I catalyst under ethylene atmosphere to yield the oxa-bowl 144 in excellent yield. Along similar lines, oxa-bowl 147 was generated through the propargylation of compound 142, and subsequent RRM of 145 followed by the DA reaction of 146 with N-phenyl maleimide (Scheme [30]).[56]

Scheme 30 Synthesis of extended diquinanes by RRM

In 2017, we reported a concise approach for the construction of intricate aza-diquinanes bearing an indole moiety by employing C–H activation and RRM/ERRM as key steps from a commercially available inexpensive simple building block such as 2-bromoaniline (148). To this end, the key precursor, indole derivative 149 was prepared from aniline derivative 148 by utilizing known procedures involving C–H activation as a key step (Scheme [31]). The indole derivative 149 was subjected to RRM with the aid of G-I catalyst under ethylene atmosphere, which generated a mixture of RRM product 150 along with the ROM product 151 in 52% and 35% yield, respectively.[57]

Scheme 31 Synthesis of benzene fused heterodiquinanes involving RRM

Subsequently, the other key starting material, N-propargyl indole derivative 152 was synthesized from the 2-bromoaniline by slightly altering the reaction sequence. Then, indole derivative 152 was treated with G-I catalyst under ethylene atmosphere to deliver the ERRM product 153 in 22% yield and ROM product 154 in 69% yield. Furthermore, the ROM product was subjected to RCM with G-II catalyst to furnish the diene 154. Finally, the DA reaction between diene 154 and tetracyanoethylene (11) under the sealed tube conditions generated the resulting DA adduct 155 in moderate yield (Scheme [32]).[57]

Scheme 32 Synthesis of heterodiquinane by enyne metathesis

An easy entry to the core structure of dendrobine[58] was developed starting with the key precursor 156, obtained by a two-step sequence from commercially available starting materials (Scheme [33]). A selective reduction of 156 with NaBH₄-I₂ at room temperature led to the formation of alcohol derivatives 157, which, upon treatment with allyltrimethylsilane (158) under the acidic conditions, provided the corresponding allyl derivative 159. Next, these allyl compounds 159 were subjected to ROM with aid of Grubbs and Hoveyda–Grubbs catalysts in ethylene atmosphere under different reaction conditions. Unfortunately, we obtained the ROM products 160 instead of the expected RRM products 161. Finally, compounds 160 were treated with G-II catalyst to generate the core of dendrobine 161 through RCM sequence (Scheme [33]).[58d]

Scheme 33 A new approach to the dendrobine core by olefin metathesis

In recent years, C ₃-symmetric frameworks have gained significant interest due to their applications in various fields of chemical sciences, especially for their optoelectronic applications. So, development of new synthetic methods are a worthy exercise. Moreover, some of these derivatives are potential ligands for catalysis.[59] Furthermore, there are limited synthetic approaches available for the construction of propellane containing C ₃-symmetric molecules. Here, we have developed a new strategy for the first time to construct N-containing star-shaped molecules bearing a propellane moiety from easily accessible substrates. To this end, we started with endo-DA adduct 162, obtained from the DA reaction between cyclopentadiene and maleic anhydride (Scheme [34]). The DA adduct 162 was treated with 4-aminoacetophenone (163) in the presence of a base under heating conditions to generate the amide product 164, which was then subjected to ROM with the aid of G-I catalyst to yield the divinyl compound 165. Trimerization of the compound 165 in the presence of ethanol and silicon tetrachloride resulted in the corresponding C ₃-symmetric compound 166 in moderated yield. Further, a sequence of allylation followed by RCM with G-II catalyst provided the N-containing C₃-symmetric molecule 167 bearing a propellane moiety in 87% yield (Scheme [34]).[60]

Scheme 34 A new approach to C ₃-symmetric heterodiquinane by ROM as a key step

Very recently, Kotha and Pulletikurti developed a facile protocol for the diastereoselective synthesis of aza-diquinane containing indolizidine derivatives via ROM (Scheme [35]). For instance, the hydroxyl compound 168 was prepared by a well-established procedure and reacted with benzofuran (169) in the presence of an excess amount of BF₃·OEt₂ (70–80 equiv) to provide the corresponding cyclized indolizidine derivative 170. Further, indolizidine 170 was subjected to ROM sequence by HG-I catalyst to deliver the divinyl compound 171. Similarly, an excess Lewis acid mediated reaction of 168 with allyltrimethylsilane (158) provided compound 172, which, under the optimized ROM conditions, gave a single diastereomer of indolizidine 173 in good yield (Scheme [35]).[61]

Scheme 35 Synthesis of diquinane containing indolizidine derivatives by ROM

Sulfone and its derivatives are ubiquitous structural motifs that are widely used in diverse biologically interesting molecules and also marketed as drugs and agrochemicals. Most importantly, the sulfone moiety is a versatile building block in organic synthesis.[62] In this context, we have developed a simple approach to diquinanes containing sulfonyl group through DA reaction and RRM. The key intermediate sulfide 174 was prepared through a sequence of known protocols in good yields (Scheme [36]).[63a] Then, sulfide 174 was oxidized using Oxone^® to get sulfone 175. Later, sulfone 175 was treated with various alkyl bromides in the presence of n-BuLi to produce the dialkylated sulfone derivatives 176a–d. Next, the compounds were subjected to RRM by treatment with the ruthenium catalyst under the ethylene atmosphere. Starting with two substrates (where n = 1 and n = 2), we obtained the RRM products 177 and 178 in 48% and 97%, respectively. However, with the other substrate (n = 3), the reaction delivered the cyclic RRM product 179 along with other products 180 and 181. Whereas, with a lengthy alkyl chain (n = 4) we obtained only the ROM product 182 rather than the RRM product (Scheme [36]).[63b]

Scheme 36 Synthesis of diquinanes containing SO₂ group via olefin metathesis

4

Synthesis of Linear Triquinanes (A3)

The development of simple approaches for the construction of linear triquinanes has attracted a great deal of attention of synthetic groups due to their potential applications in natural and non-natural products synthesis. In 1984, a concise synthetic approach to linear triquinanes from pentacyclic system 183 via flash vacuum pyrolysis (FVP) and metal promoted cleavage was disclosed (Scheme [37]). The FVP of 183 at a higher temperature (560 °C) furnished the corresponding linear triquinane 184 in 78% yield, which was further subjected to catalytic hydrogenation using Pd/C to furnish triquinane 185 through the 1,4-reduction of conjugated diene system. Alternatively, a slightly different approach has been designed to synthesize an important triquinane derivative 188. For instance, alkali metal-mediated reduction of 183 provided a mixture of tricyclic alcohols 186 and 187 in 50% yield. The oxidation of compounds 186 and 187 with PCC followed by hydrogenation with Pd/C afforded the corresponding saturated triquinane 188 (Scheme [37]).[64]

Scheme 37 Synthesis of linear cis-syn-cis triquinanes via FVP and C–C bond cleavage

Additionally, a facile procedure for the construction of a linearly fused tricyclopentanoid framework by using the reductive C–C bond cleavage of commercially available Cookson’s dione 189 was reported. In this strategy, the Zn-dust-mediated reaction of 189 in acetic acid under sonication yielded the corresponding tetracyclic dione 190 in 90% yield through C1–C7 bond reduction. The reaction of 190 with an excess amount of Na-K alloy in the presence of trimethylsilyl chloride gave the tricyclic dione 191 via C9-C10 bond reduction along with the pentacyclic diol 192. The yields of these compounds 191 and 192 were dependent on the nature of solvent used for quenching. Subsequently, dione 193, under similar reaction conditions, delivered the corresponding triquinane 195 along with the byproduct 196 (Scheme [38]).[65] These triquinanes 191 and 195 are important synthons to develop a library of polycycles through a variety of chemical transformations. For example, FI sequence is used to synthesize fused indole derivatives from these compounds. Along similar lines, linear triquinanes 191 and 199 were synthesized in good yields from the corresponding cage diones 197 (Scheme [39]).[66] In case of methyl group substitution, we observed another minor product 200.

We also described a facile Lewis acid catalyzed rearrangement of the substituted pentacyclic diones to the corresponding linear triquinanes. To this end, treatment of 193 with BF₃·OEt₂ resulted in a mixture of products 201 and 202 along with a linear triquinane 203 in 15%, 25% and 20% yields, respectively. The structures of these compounds were determined by NMR spectroscopic studies. The hexacyclic propellane derivative 201 was formed through a Cargill-type rearrangement of compound 193 (Scheme [40]). The hydrogenation of 203 with Pt₂O gave the corresponding saturated triquinane derivative.[67]

Scheme 38 Synthesis of linear triquinane by reductive C–C bond cleavage

Scheme 39 Synthesis of linear triquinanes from Cookson’s dione

Scheme 40 Synthesis of linear triquinane 203 by rearrangement approach

Kotha and Manivannan successfully synthesized functionalized linear triquinanes starting with the known substrate 6,7-dimethyl methanoanthracene derivative 204. In this regard, the intramolecular cycloaddition of 204 under photochemical irradiation leads to the generation of the required compound 206 in 54% yield along with the formation of aromatized compound 205 in 11% yield. This may be due to the over-oxidation during the preparation of 205. Ruthenium-catalyzed C–C bond cleavage of dione 206 affords the corresponding pentacyclic derivative 207. Later, FVP of 207 followed by hydrogenation with Pd/C yielded the saturated dione 209 in 64% yield (Scheme [41]).[68]

Scheme 41 Synthesis of linear triquinane by photothermal olefin metathesis

We subsequently reported a simple synthetic approach to cis-syn-cis triquinane frameworks starting with the cage diones under MWI conditions. Cage diones were generated from easily accessible inexpensive materials such as 1,3-cyclopentadiene and p-benzoquinone derivatives through a DA reaction and [2+2] photocycloaddition. The halogen-substituted cage dione 210 was subjected to a photothermal olefin metathesis reaction under MWI conditions in diphenyl ether (DPE) to generate the corresponding halotriquinanes 211 and 212 in good yields (Scheme [42]). Whereas, non-halogenated cage diones (197a; R¹ = R² = Me and 197b; R¹ = H, R² = Me) under similar reaction conditions provided a mixture of triquinanes (213a, 214a and 213b, 214b, Scheme [43]). Interestingly, other diones 197 generated selectively cis-syn-cis triquinanes 213c–e under these conditions (Scheme [43]). It is worth mentioning that a photothermal olefin metathesis of cage diones under conventional heating/FVP conditions led to the generation of cis-syn-cis triquinanes selectively. Whereas under MWI conditions, double bond isomerized products were obtained along with normal products. Afterward, a photothermal olefin metathesis of cage diones 215 and 219 bearing spiro center at the bridgehead position under MWI conditions delivered a mixture of triquinanes 216–218, and 220 and 221 as shown in Scheme [44] and Scheme [45].[69]

Scheme 42 Synthesis of halotriquinanes by photothermal metathesis under MWI conditions

Scheme 43 Synthesis of triquinane derivatives under MWI conditions

Scheme 44 Synthesis of linear triquinanes containing a cyclopropane unit

Scheme 45 Synthesis of tetramethyl linear triquinanes under MWI conditions

Cage polycyclic compounds are useful synthons to assemble various biologically interesting triquinane containing natural and non-natural products. In this context, functionalized linear triquinanes were generated by utilizing photothermal olefin metathesis and CM from easily accessible substrates. The photothermal olefin metathesis reaction of cage compound 222 under MWI conditions gave the linear cis-syn-cis triquinane compound 223 in 43% yield, which, on treatment with cis-1,4-diacetoxy-2-butene (224) with the aid of modified Grubbs catalyst 225, provided the corresponding acetyl triquinane 226 through CM sequence. A similar strategy was realized to generate monoallyl triquinanes 230 and 231 prepared from a known DA adduct 227 through a FVP followed by CM sequence with the aid of modified Grubbs catalyst 225. Moreover, the cage compound 229 was prepared through the CM and [2+2] photocycloaddition of compounds 231 and 228, respectively (Scheme [46]).[70]

Scheme 46 Synthesis of cis-syn-cis triquinanes by photothermal olefin metathesis and CM

Recently, we investigated a versatile approach to construct a variety of linear triquinanes using stereochemically defined DA adduct 232 as a starting material, obtained from the endo- and exo-dicyclopentadiene-1-one.[71] Treatment of 232 with allyl bromide (14) in the presence of NaH/KH provided monoallyl compound 233, which, upon the metathesis sequence with G-II catalyst, gave the corresponding ROM product 234 in moderate yield rather than the expected RRM product. Later, ROM of compound 232 generated the tetravinyl derivative 235, which, upon the Grignard reaction with allylmagnesium bromide (133), furnished the allyl substituted hydroxy derivative 236. Subsequent RCM with G-II catalyst in toluene under heating conditions led to the formation of cyclohexane fused triquinane 237 in 89% yield. Similarly, Grignard addition followed by RCM of linear triquinane 238 provided the corresponding cyclohexane fused triquinane 240 in good yield (Scheme [47]).[72]

Scheme 47 A ROM approach to triquinane 234 and beyond

Along similar lines, we prepared the triquinane 243 starting with a key precursor 241, which was obtained by a sequence of known chemical transformations starting with readily available basic materials. Grignard addition of compound 241 with allylmagnesium bromide (133) generated the corresponding allyl alcohol 242, which, upon treatment with G-II catalyst, delivered the triquinane derivative 243 through RRM sequence along with the ROM product 244 (Scheme [48]).[49]

Scheme 48 Synthesis of triquinane derivative 243 by tandem metathesis

Heteropolyquinanes involve a fused cyclopentane system containing at least one heteroatom such as N/O/S in their structure. These honored structures are found in numerous drug-related molecules and natural products. In view of their proven utility, there is a need to develop more efficient synthetic strategies to access hetero-polyquinanes for ‘drug discovery’. One of the most popular synthetic approaches to introduce a nitrogen atom in the molecule is by FI sequence as key step starting with keto substrates. It is well known that the indole unit is a privileged scaffold in drug discovery due to its presence in several bioactive natural products and drugs. To this end, to expand heteropolyquinanes library, our group envisioned a systematic approach to indole based aza-triquinanes from readily available carbonyl synthons via FI and RRM as key steps. The Zn-AcOH mediated selective reduction of a conjugated double bond of exo-tricyclic enone 245 produced the saturated ketone 246. FI of 246 with phenylhydrazine hydrochloride (247) in the presence of l-(+)-tartaric acid (TA) and N,N′-dimethylurea (DMU) furnished the corresponding fused indole derivative 248. The indole derivative 248 was then treated with allyl bromide (14) and propargyl bromide (5) with NaH to generate the corresponding N-allyl and N-propargyl indole derivatives 249 and 251, respectively, in good yields. Metathesis reaction of indole derivatives 249 and 251 with G-I catalyst under the ethylene atmosphere selectively gave the corresponding ROM products 250 and 252 rather than the expected RRM products. Further, treatment of the compound 252 with the aid of G-II catalyst furnished the enyne metathesis (EM) product 253 in good yield without new ring formation (Scheme [49]).[73]

Scheme 49 New approach to aza-triquinanes by ROM

To expand the scope of this methodology, several indole derivatives containing longer N-alkyl chains were prepared and subjected to ruthenium-catalyzed metathesis under different conditions. Interestingly, RRM product 255b was obtained selectively when n = 2. Surprisingly, when n = 1, we observed both RRM and ROM products 255a and 256a, and with substrate when n = 3, we obtained ROM product 256b selectively. Subsequently, the RCM reaction was carried out with longer chain N-alkenyl ROM indole derivatives 256. It is worth mentioning that the RCM product 255b was obtained only when the allyl chain length is suitable (n = 2), which was confirmed by single-crystal X-ray studies (Scheme [50]).[73]

Scheme 50 Synthesis of aza-triquinane fused macrocycles

Later, we successfully synthesized aza-triquinane 260 starting with the key endo precursor 47 through a four-step sequence. The reduction of compound 47 using Zn-AcOH under reflux conditions furnished the corresponding saturated ketone 257, which was then subjected to FI cyclization with phenylhydrazine hydrochloride (247) in the presence of a low-melting mixture of TA and DMU to generate the indole derivative 258. The indole derivative 258 was treated with allyl bromide (14) to generate the N-allyl indole 259. The RRM of compound 259 with G-I catalyst under ethylene atmosphere provided the aza-triquinane derivative 260 in excellent yield (Scheme [51]).[51]

Scheme 51 Synthesis of aza-triquinane 260 by RRM

5

Synthesis Spiro Triquinanes (A4)

By extension of this metathesis strategy an unsaturated spiro diquinane 262 was produced from a key precursor exo-dicyclopentadiene-1-one 245. The reduction of key precursor 245 with Zn-AcOH followed by allylation delivered the corresponding diallyl norbornene derivative 261. Later, the diallyl compound 261 was subjected to RCM with the aid of G-I catalyst to yield the unsaturated spiro triquinane 262, which was further utilized to generate a library of new polyquinanes (Scheme [52]).[33]

Scheme 52 Synthesis of vinyl substituted spiro triquinane by RCM and ROM

Next, the same strategy was extended to assemble cyclohexane fused with spiro triquinane derivative 266, which resembles the core structure of natural products magellanine (N6) and magillaninone (N7).[26] To begin with, Zn-AcOH reduction of endo-dicyclopentadiene-1-one 47 gave the saturated keto derivative, which, on treatment with allyl bromide (14) in the presence of KH, delivered the triallyl compound 263. The metathesis sequence of compound 263 with G-II catalyst produced the cyclized compound 264 through RCM followed by ROM. Incorporation of one more allyl group on compound 264 was archived by Grignard addition with allylmagnesium bromide (133). Spiro compound 265 was subjected to RCM with the aid of G-II catalyst to yield the corresponding cyclohexene derivative 266 in 89% (Scheme [53]).[33]

Scheme 53 Synthesis of spiro triquinane by metathesis

The key RCM precursor 48 was obtained from compound 47 through reduction followed by diallylation. Metathesis of 48 with the G-I catalyst gave the corresponding unsaturated spiro derivative 267 involving RCM and ROM. Further, the same triquinane 267 was produced by the ROM of norbornene derivative 49 with G-II (Scheme [54]).[33]

Scheme 54 Synthesis of spiro triquinane 267 by RCM and ROM

Alternatively, vinyl substituted triquinanes 271 and 272 were synthesized from a key precursor exo-dicyclopentadiene-1-one 245 by applying the metathesis sequence. For this purpose, 1,4-addition of compound 245 with vinylmagnesium bromide (268) gave vinyl compound 269, which, upon allylation in the presence of NaH using allyl bromide (14), furnished the diallyl compound 270. The norbornene derivative 270 was treated with G-II catalyst delivered a mixture of linear and spiro triquinanes 271 and 272, respectively, through RCM and ROM sequence (Scheme [55]).[33]

Scheme 55 Synthesis of linear and spiro triquinanes via RCM

A convenient approach to spiro and linear triquinanes was developed by employing endo-tricyclic vinyl ketone 273 through RCM as a key step. The vinyl compound 273 was obtained from the endo-intermediate 47 via 1,4-addition of vinylmagnesium bromide (268). Allylation of vinyl compound 273 with allyl bromide (14) in the presence of NaH gave diallyl compound 274 and with KH gave triallyl compound 277. RCM of compound 274 with G-II catalyst furnished a mixture of unsaturated spiro- and linear-triquinanes 275 and 276 in 10% and 68% yields, respectively. Similarly, RCM of compound 277 with G-II catalyst provides a mixture of spiro- and linear-triquinanes 278 and 279 in 33% and 46% yield, respectively. Further, a library of new compounds were prepared by utilizing these final structures through hydrogenation as well as RCM sequence (Scheme [56]).[33]

6

Synthesis of Angular Triquinane (A5) Systems

Another interesting application of metathesis shown here is the synthesis of basic skeletons of natural products subergorgic acid and cameroonanol.[74] As described with the exo substrate 245, reduction followed by methylation of exo-enone 245 gave the corresponding dimethyl keto derivative 280, which was treated with allyl bromide (14) in the presence of KH to produce allyl compound 281. RRM of 281 with the G-II catalyst under ethylene atmosphere yielded the angular triquinane 282 in 82% yield, which is similar to the core structure of natural product subergorgic acid.[73] Further, reduction of angular triquinane 282 with DIBAL-H (141) provided the corresponding alcohol 283, which resembles the core structure of natural product cameroonanol (Scheme [57]).[33]

Scheme 56 A simple approach to linear and spiro triquinanes via tandem metathesis

Scheme 57 Synthesis of angular triquinane via tandem metathesis

Scheme 58 A simple strategy to access the natural product subergorgic acid (N71) core

As previously described, the keto derivative 284, containing cyclopropane, was obtained by the a reported procedure starting with exo-enone 245.[45] The tetracyclic compound 284 was treated with G-I catalyst to deliver the ROM product 285, which, on allylation with allyl bromide (14) in the presence of KH, provided the allyl precursor 286. The RCM of unsaturated compound 286 with the G-I catalyst gave the angular triquinane 287 in good yield (Scheme [58]).[33]

7

Synthesis of Hexahydro-2′H-spiro[cyclopentane-1,1′-pentalene] (A6) Ring System

Scheme 59 Synthesis of spiro triquinane via Weiss–Cook reaction

The bis-enol ether 99, synthesized through Weiss–Cook reaction, was then reacted with allyl bromide (14) in the presence of potassium tert-butoxide followed by the acid-catalyzed ester hydrolysis and decarboxylation to give non-separable diallyl quinanes 288 and 289. The ozonolysis of diallyl compound 288 provided the stereoisomeric mixture of exo/endo bis-aldehyde 290 in 98% yield. Later, diketo diol was intended to be accessed by bisaldolization of 290 through cyclization under acidic conditions. Unfortunately, bis-aldehyde 290 provided the transannular product 291 rather than the expected diketo diol (Scheme [59]).[75]

Based on our experience on FI, the spiro-indole derivatives 294–296 and 299 were synthesized in good yields in a three-step sequence through FI and RCM. The FI of substituted 1-indanones 60 with N-methylphenylhydrazine (292) provided the corresponding indole derivatives 293. Subsequently, allylation of indole derivatives 293 with allyl bromide (14) followed by RCM with the aid of G-I catalyst yielded the target spiro-indole derivatives 294–296 (Scheme [60]). The same method has been applied for the generation of an isomeric spiro-indole derivative 299 from 2-indanone (297, Scheme [61]).[76]

Scheme 60 Synthesis of spiro indole derivative 294–296

Scheme 61 Synthesis of spiro indole derivative 299

Furthermore, the bromo compound 295 was subjected to SM coupling with diverse aryl/heteroaryl-boronic acids 58 to synthesize a library of indole derivatives 300a–k in good to excellent yields (Scheme [62]). Such compound libraries offer potential candidates for drug discovery programs.[76]

Scheme 62 A facile approach to spiro indole derivatives 300a–k

8

Synthesis of Dispiro[4.1.4⁷.2⁵]tridecane (A7) Ring System

A conceptually different strategy has been devised to construct various complex bis-armed spiro-triquinanes by employing a two-directional [2+2+2] co-trimerization and [4+2] cycloaddition reaction as key steps. In this context, the building block 301 was synthesized from carbonyl compounds by tetrapropargylation (Scheme [63]). Tetra-ol derivatives 302 were synthesized by the reaction of 301 with 2-butyne-1,4-diol (7) in the presence of Wilkinson’s catalyst and a catalytic amount of titanium isopropoxide, which, on treatment with phosphorus tribromide, gave 303. The structural isomers of sultine derivatives 304–306 were obtained with rongalite from the corresponding bromo derivatives 303. The aromatized products 307 were obtained through a sequential DA reaction of 304–306 with different dienophiles (11) followed by DDQ oxidation. In this event, we also observed the formation of rearranged sulfone derivatives 308 as minor products. This observation prompted us to investigate the selective synthesis of sulfone derivatives due to their biological and drug-like properties. The bis-armed spirosulfone derivatives 308 were generated in good yields from 304–306 by using a two-directional [2+2+2] co-trimerization under reflux conditions in toluene (Scheme [63]).[77]

9

Synthesis of Hexahydro-1H-3a,7a-propanoindene Ring System

A facile synthetic approach has been reported to access the triquinane derivative from exo-nadic anhydride 309, easily obtained by a reported procedure. Next, it was subjected to allylation with allyl bromide (14) in the presence of NaHMDS to furnish the diallyl compound 310 with retention of configuration at the ring junction. Later, the diallyl compound 310 was treated with G-I catalyst under the ethylene atmosphere to produce the propellane derivative 312 in 60% yield through ROM and RCM process along with a minor amount of RCM product 311 (Scheme [64]).[78]

Scheme 63 Synthesis of bis-armed spiro derivatives

Scheme 64 Synthesis of propellane derivative 312

10

Synthesis of Linear Tetraquinanes (A11 and A12)

In 1988, an efficient approach was reported for the preparation of tetraquinane 317 using the Weiss–Cook reaction as a key step. The reaction of 2,6-diallyl tetraester 104 with hydrobromic acid (313) gave the dibromo derivative 314 in 68% yield. Finally, the SmI₂ (315) and HMPA (316) mediated cyclization of dibromo compound 314 gave a mixture of stereoisomeric tetracyclic diol 317 in an approximate ratio of 15:2. Among these, the cis-cisoid-cis-cisoid isomer formed as a major product (Scheme [65]).[79]

Scheme 65 Synthesis of tetraquinane derivative 317

The tricyclic keto olefin 318, on reaction with dichloroketene, derived from trichloroacetyl chloride (319) in the presence of zinc, delivered the corresponding regioisomers in 1:1 ratio, which, on ring expansion with diazomethane followed by the dechlorination with Zn-AcOH, gave the diketo-tetraquinane 320 (Scheme [66]).[65]

Scheme 66 Synthesis of tetraquinane 320

Scheme 67 Synthesis of tetraquinane derivatives 324 and 325

We reported a concise approach to several polyquinanes via cyclopentane annulation using inexpensive starting materials. In this regard, readily accessible bicyclo[3.3.0]octane derivative 102 was converted into diallyl diol 321 by the Grignard reaction involving allyl bromide (14) and magnesium. Later, the diol 321 underwent a hydroboration-oxidation sequence with NaBH₄ and Jones reagent (322) to furnish the lactone 323, which underwent rearrangement with methanesulfonic acid/P₂O₅ to produce a mixture of tetracyclic enones 324 and 325 (Scheme [67]). Finally, Pd/C mediated hydrogenation gave the corresponding saturated tetraquinanes.[80]

Scheme 68 Synthesis of indole-based [n.3.3] propellanes

In 2013, we developed a simple protocol for the construction of synthetically challenging indole-based [n.3.3] propellanes through a two-fold FI and RCM as key steps. The cyclopentane-fused bis-indole 326 was synthesized via FI of diketone 102 with N-methylphenylhydrazine (292), which further oxidized with SeO₂ to afford diindole derivative 327. Later, RCM precursors 329 and 332 were generated by alkylation reaction with alkenyl bromides such as 14 and 331. Next, these alkene derivatives 329 and 332 underwent a metathesis sequence with the aid of the G-II catalyst followed by hydrogenation to provide the indole-based propellanes 330 and 333 in excellent yields (Scheme [68]).[81a] Alternatively, indole-based propellanes 334 and 335 were prepared by a different approach through FI of propellane 102b with 292 (Scheme [69]).[81b]

Diindole-fused quinanes were successfully synthesized by using a combination of Weiss–Cook reaction and FI, starting with easily available synthons. Diindole-fused diquinane 337 was synthesized through the acid mediated FI of cis-bicyclo[3.3.0]octane-3,7-dione (102) with phenylhydrazine (336). The dimethyl diindole derivative 326 was prepared in good yield by methylation of free N-H of diindole 337. Alternate approach has been developed to construct a mixture of cis- and trans-diindole-fused diquinanes 326 and 338. This approach involves the FI of 102 with N-methylphenylhydrazine (292) using l-(+)-TA and DMU. Interestingly, the deep eutectic mixture gave thermodynamically less favorable product 338, which could not be obtained by conventional FI sequence (Scheme [70]).[81a] [82]

Scheme 69 Synthesis of indole-based propellanes 334 and 335

Scheme 70 Synthesis of diindole-fused diquinanes

Scheme 71 A facile approach to bis-spiro tetraquinane 340 and bis-spiro propellane 342

11

Synthesis of Tetrahydro-1′H,3′H-dispiro[cyclopentane-1,2′-pentalene-5′,1′′-cyclopentane] (A13) Ring System

An efficient and simple strategy was disclosed to construct the bis-spiro tetraquinane and bis-spiro propellane derivatives by our group in 2014 from commercially available starting materials. The pivotal diketo compound 132 was prepared from (1Z,5Z)-cycloocta-1,5-diene through a known procedure. A carefully controlled allylation of 132 with allyl bromide (14) in the presence of NaH provided the corresponding RCM precursors, tetraallyl compound 339 and hexaallyl compound 341 in 6 and 24 hours, respectively. Interestingly, metathesis sequence of compounds 339 and 341 with the help of G-I catalyst followed by hydrogenation with Pd/C afforded the saturated bis-spiro tetraquinane 340 and bis-spiro propellane derivative 342 in good yields, respectively (Scheme [71]).[83]

12

Synthesis of Decahydro-1H,8H-dicyclopenta[a,h]pentalene (A14) Ring System

A useful synthetic approach has been established to access tetraquinanes and propellanes in good yields through a ROM and RCM. The construction of fused heterocyclic tetraquinane derivatives 345 begins with exo-nadic anhydrides 309, which is easily obtained by a known sequence. To this end, we performed the key ROM reaction initially with various substituted exo-nadic anhydrides 309 by using G-II catalyst to afford the divinyl compounds 343. Allylation of 343 followed by RCM with the aid of G-II catalyst provides the desired tetraquinanes 345 as the major product along with minor amounts of propellane derivatives 312 and 346. The RCM reaction was optimized by studying several reaction conditions, including changing catalysts under different conditions. In this regard, screening revealed that the use of G-II catalyst in DCM is a better choice to generate the hetero-tetraquinanes as major products (Scheme [72]).[78] Another interesting example of this approach is illustrated in the synthesis of hetero-bis-tetraquinane 348, tetraquinane-propellane 349 and bis-propellane 350 (Scheme [73]).[78]

Scheme 72 Synthesis of hetero-tetraquinanes 345 and hetero-propellanes 312 and 346

Scheme 73 Synthesis of diverse hetero-bis-tetraquinane derivative

13

Synthesis of Dodecahydro-1H-dicyclopenta[a,d]pentalene (A15) Ring System

Another synthetically intricate approach to fused tetraquinane derivative 353 was envisioned from stereochemically well-defined DA adduct 351. Alkylation of 351 with allyl bromide (14) in the presence of KH led to the generation of monoallyl compound 352 in 46% yield. Next, monoallyl derivative 352 was subjected to RRM by exposure to the G-II catalyst to obtain the tetraquinane 353 in excellent yields. The catalyst loading had not much influence on the reaction efficacy (Scheme [74]).[72] Late-stage manipulation of allyl derivative 352 by one-step metathesis process to generate a meaningful and densely functionalized natural product like cyclopentane core (i.e., 353) is not a trivial exercise. This work highlights the power of RRM and the value of simple building blocks available by DA chemistry.

Scheme 74 Synthesis of fused tetraquinane derivative 353

Subsequently, the triquinane 235, on reaction with allyl bromide (14) in the presence of an excess amount of KH under heating conditions, yielded the diallyl compound 354. Later, RCM of 354 with the aid of G-II catalyst in dry toluene at 70 °C gave the tetraquinane 355 in 84% yield (Scheme [75]).[72]

Scheme 75 Synthesis of fused tetraquinane 355

Scheme 76 Synthesis of tetraquinane 358 and spiro tetraquinane 357 by tandem metathesis

Two unsaturated tetraquinane derivatives were synthesized by our group by performing conjugate addition and allylation followed by RRM using the key precursor exo-dicyclopentadiene-1-one (245). For this purpose, keto compound 278 was prepared through the 1,4 vinyl Grignard addition of the enone 262. Next, allylation of the compound 278 with allyl bromide (14) in the presence of a large amount of KH delivered the triallyl derivative 356 and it was treated with various ruthenium catalysts, which gave a mixture of unsaturated spiro- and angular-tetraquinanes 357 and 358. In case of G-I catalyst, we observed a better yield of tetraquinanes 357 (37%) and 358 (52%). It is worth mentioning that the structure of compound 358 resembles the core structure of the natural product crinipellin (Scheme [76]).[33]

14

Synthesis of Octahydro-1′H-spiro[cyclopentane-1,2′-cyclopenta[c]pentalene] (A16) Ring System

We have also prepared the unsaturated spirotetraquinane 360 from the key precursor 245 by applying the RRM strategy as a key step. The selective reduction of compound 245 in the presence of Zn-AcOH furnished the norbornene fused keto compound 246, which, upon allylation in the presence of KH at higher temperature, led to the formation of triallyl derivative 359 in good yields. Finally, compound 359 was treated with G-II catalyst under ethylene atmosphere to give the spiro tetraquinane 360 in 91% yield through RRM sequence (Scheme [77]).[33]

Scheme 77 Synthesis of spiro tetraquinane via tandem metathesis

15

Synthesis of Decahydrospiro[cyclopentane-1,7′-cyclopenta-[a]pentalene] (A17) Ring System

Scheme 78 Synthesis of diallyl spiro tetraquinanes

We have reported a concise strategy to diverse quinane frameworks from cage diones under green reaction conditions. To this end, several cage diones were prepared from a sequence of known chemical transformations. The cage dione 361 under MWI at 150 W and 180–240 °C provided a mixture of spiro-tetraquinanes 362 and 363 in 29% and 47% yields, respectively (Scheme [78]). Subsequently, the same strategy has been applied to generate diverse tetraquinanes and their isomerized products 365–367 in good yields, which are useful precursors for natural product syntheses (Scheme [79]).[69]

Scheme 79 Synthesis of tetraquinanes

16

Synthesis of Compact Tetraquinane (A18)

Triquinacane based tetracyclic compound 371 was efficiently synthesized by using the diastereomeric mixture of 2,6-dially diketo compound 104. Initially, the diastereomeric mixture 104 was oxidized on a small scale under ozonolysis conditions to deliver the epimeric mixture of dialdehydes 368 in 90% yield. Unfortunately, on large-scale, the reaction was sluggish in nature and the product was obtained in poor yields. To resolve this issue, ozonolysis reaction was performed instead of OsO₄ oxidation by using dimethyl sulfide (DMS) to diminish the oxidative intermediates. However, moderate amounts of other by-products like peracetals or keto acetals were also observed along with the two epimeric aldehydes 368. Interestingly, the ozonolysis reaction provided a mixture of both epimeric aldehydes 368 cleanly in 90% yield by replacing the DMS with trimethyl phosphite, which presumably reduces the formation of by-products. Further, the mixture of bis-aldehyde 368 underwent intramolecular aldol condensation in the presence of 2N HCl to provide a mixture of tetraquinane 369 in 35%, which, on reduction with borane-THF (370) gave the tetraol derivative 371. Surprisingly, an unprecedented tetraquinane 372 was obtained instead of the expected dehydrative compound when tetraol 371 was reacted with HMPA (Scheme [80]).[79]

Scheme 80 Synthesis of tetraquinane 371

In connection with our interest in the synthesis of new cyclopentanoids, initially we focused on the construction of an important target pentaquinane. For this purpose, we performed a PTSA catalyzed reaction of dione 373 with the mixture of allyl alcohol (103) and 2,2′-dimethoxypropane (374) under reflux in toluene to achieve diallylation. Unfortunately, we obtained a mixture of products such as monoallyl triquinane 375 and tetracyclic ether 376 rather than the expected diallyl triquinane (Scheme [81]).[68]

Scheme 81 Allylation of triquinane via CR

To further expand the synthetic applicability of the cage dione 193, ‘belted’ triquinane bis-enone 214c was synthesized through [2+2] cycloreversion under FVP conditions at 550 °C in 70% yield, which undergoes a nucleophilic addition with MeMgI (377) to provide the oxa-tetraquinane derivative 378 (Scheme [82]).[67]

Scheme 82 Synthesis of oxa-tetraquinane 378

17

Synthesis of Higher Polyquinanes

A new approach for the synthesis of novel C₁₅-pentaquinane was started with the rearrangement of cage compound 379 with Zn-AcOH to provide an annulated trishomocubane derivative 380. Reaction of 380 with NaOMe-MeOH under reflux conditions provided the mixture of the annulated cages 381 and 382 in 45% and 30% yields, respectively. Reduction of 381 with Na-K alloy-Me₃SiCl in dry toluene led to the formation of expected C₁₅-polyquinane 383 in 50% yield; the structure was unambiguously established from both spectral and single-crystal X-ray diffraction studies (Scheme [83]).[84] Along similar lines, a facile approach to the substituted pentaquinane 384 form the cage dione 382 in the presence of Na-K-alloy-Me₃SiCl was reported.

Scheme 83 Synthesis of C15-polyquinanes starting with cage compound 379

Subsequently, we also investigated the synthesis of pentaquinanes from the DA adduct 351 through RRM/RCM sequence. For this purpose, treatment of compound 351 with allyl bromide (14) in the presence of a large amount of KH in THF at 140 °C provided the diallyl compound 385, which, upon RRM with G-II catalyst, led to the generation of pentaquinane 387 in excellent yield. Further, ROM of 351 with G-I catalyst gave the triquinane 238, which, upon allylation with allyl bromide (14) in the presence of 12 equivalents of KH, gave the diallyl precursor 386 in 52% yield. The RCM of compound 386 with G-II catalyst furnished the pentacyclic compound 387 in excellent yield (Scheme [84]).[72] The architecture of 387 is intriguing. It can be viewed as a fusion of two angular triquinanes with a common cyclopentane ring. Alternatively, it can be considered as a combination of linear triquinane and two angular triquinanes. By any standards it is not an easy task to design such a target by traditional synthetic routes. This example demonstrates the power of the rearrangement approach to design complex targets that contain eight chiral centers.

Scheme 84 Synthesis of pentaquinane 387 via olefin metathesis

A convenient strategy to synthesize hexaquinane 393 has been reported by a series of simple chemical transformations from an easily accessible tetraquinane 388. The Grignard reaction of diketone 388 with allyl bromide and magnesium provided a diastereomeric mixture of homoallylic alcohols 389 and 390 in 1:8 ratio. Later, 391 was subjected to a hydroboration–oxidation with sodium borohydride and Jones reagent (322) to give the dilactone 391 in 94% yield. Finally, 391 was treated with methanesulfonic acid and P₂O₅ to provide the rearranged conjugated dienone 392, followed by hydrogenation of the conjugated double bond, which led to the formation of hexaquinane 393. The stereochemistry of 393 was established by single-crystal X-ray diffraction studies (Scheme [85]).[85]

Scheme 85 Synthesis of hexaquinane 393

Scheme 86 Synthesis of hexaquinanes 397 and 398

Along similar lines, the reaction of dione 394 with an excess amount of allylmagnesium bromide (133) furnished a diastereomeric mixture of homoallylic alcohol 395. Then, hydroboration followed by oxidation with Jones reagent (322) provided the lactone 396, which was then treated with methanesulfonic acid/P₂O₅ under heating conditions to afford dienone 397 along with a novel transannular product 398 in equal proportions. The hydrogenation of 397 with Pd/C provided the saturated C₂₀-hexaquinane (Scheme [86]).[80a] Synthesis of these advanced precursors (e.g. 393, 397, and 404) to dodecahedrane (T1, Figure [4]) containing all twenty carbons demonstrate the power of reiterative processes and a ‘two-directional functionalization strategy’. Interestingly this is nothing but ‘Brevity in Reaction Design’.[80b]

Along similar lines, the allyl Grignard reaction of 133 and tetraquinane 399 afforded a mixture of diallyl diol 400 and transannular product 401 in 45% and 30% yields, respectively. Hydroboration–oxidation sequences of 400 and 401 produced the corresponding rearrangement lactones 402 and 403. Later, 403 was subjected to rearrangement with methanesulfonic acid/P₂O₅ to produce the curved C₂₀-hexacyclic dione 404 (Scheme [87]).[86]

Next, we describe an efficient synthetic route to spiro polyquinanes from diketo compounds via RCM. To this end, allylation of dione 373, in the presence of sodium hydride (NaH), provided the hexaallyl precursor 405, which underwent RCM with the aid of G-I catalyst followed by hydrogenation to furnish the corresponding saturated bis-spiro polyquinane 406 in good yield. The same approach was applied to construct bis-spiro polyquinane derivatives 409 in good yields starting from the dione 407 (Scheme [88]).[87]

A synthetically useful strategy has been investigated to assemble interesting aza-polyquinane/propellane derivatives via FI as a key step starting with Weiss–Cook dione such as 410. This approach is robust and generated the isomeric mixture of bis-indole derivatives 411 and 412 through two-fold FI of tricyclic [4.3.3]propellane dione (410) with N-methylphenylhydrazine (292; Scheme [89]).[88]

Scheme 87 Synthesis of hexaquinane 404

Scheme 88 Synthesis of bis-spiro polyquinanes

Scheme 89 Synthesis of indole-based propellanes

Subsequently, to expand the scope of this strategy and to synthesize a variety of polycyclic bis-indole derivatives 413 and 414 in a five-step sequence from easily accessible substrates. The reaction of 383 with N-methylphenylhydrazine (292) in the presence of a low-melting mixture of TA and DMU produced the bis-indole derivative via twofold FI, which, on hydrogenation, gives the corresponding saturated bis-indole based polyquinane 413. Surprisingly, FI of methoxy substituted pentacyclic dione 384 provided the unexpected mono-indole derivative 414 instead of bis-indole derivative due to the steric factor induced by methoxy group (Scheme [90]).[88]

Scheme 90 Synthesis of indole-based polyquinanes

Another interesting entry to bis-indole derivatives was disclosed using FI and RCM. Starting with cis-syn-cis-triquinane-dione 373, the bis-indole derivative 415 was synthesized through FI with phenylhydrazine (247). Reaction of bis-indole 415 with allyl bromide (14) in the presence of NaH produced the N-allyl derivative 416, which, on treatment with G-II catalyst, afforded the RCM product 417. Then hydrogenation with Pd/C led to the bis-indole based macrocycle 418 in 95% yield (Scheme [91]).[87]

Scheme 91 Synthesis of aza-polyquinane containing bis-indole

In connection with our interest in hetero polyquinanes, we also investigated the synthesis of indole-based polyquinanes from readily available carbonyl compounds via FI. To this end, the dione 394 was prepared from Weiss–Cook dione 102 as shown earlier. Later, the FI of dione 394 with N-methylphenylhydrazine (292) gave the corresponding bis-indole polyquinane 419 in 73% yield. Similarly, the FI of dione 421 with N-methylphenylhydrazine (292) produced the diaza polyquinane 422 (Scheme [92]). The same strategy was applied for the construction of indole-based propellanes, which, on further oxidation with SeO₂, gave the corresponding keto propellanes in good yields.[89]

To expand the library of polyquinane containing bis-indoles via FI and RCM as key steps, we used the tetracyclic dione 190 as a starting material. In this regard, the compound 190 was subjected to the FI with N-methylphenylhydrazine (292) to give a mixture of polyquinane bearing indole derivatives 423, 424 and 425 (Scheme [93]). Afterwards, the key precursor 426 was prepared from dione 190 and subsequent base mediated allylation. Next, the diallyl compound 426 was treated with a low-melting mixture of TA and DMU to generate the aza-polyquinane 427 composed of a bis-indole unit. The RCM of bis-indole 427 with G-II catalyst and subsequent hydrogenation with Pd/C furnished the macrocycle fused bis-indole derivative 428 in good yield (Scheme [94]).[90]

Scheme 92 Synthesis of indole-based polyquinanes

18

Conclusions

In conclusion, cyclopentanoids are privileged structures that are present in a numerous bioactive molecules. This review demonstrates a collection of our unique strategies for the construction of cyclopentanoids and their hetero derivatives by using various types of named or unnamed reactions. Based on these examples, it is evident that along with previous methods we added some new protocols for the synthesis of these intricate cyclopentanoids. Herein, we have summarized the use of various types of metathesis and cycloaddition protocols as key steps to construct the stereochemically well-defined cyclopentanoids from readily available starting materials. These new strategies may find a broad range of synthetic applications in natural product synthesis, bioorganic chemistry and material science, which, in turn, should catalyze further developments in this area.

Scheme 93 Synthesis of polyquinane-containing indole moiety

Scheme 94 Synthesis of macrocycle-containing cyclopentane rings

19

Acronyms

BTEAB: benzyltriethylammonium bromide

BTEAC: benzyltriethylammonium chloride

CpCo(CO)₂: cyclopentadienylcobalt dicarbonyl

CR: Claisen rearrangement

DEAM: diethyl acetamidomalonate

DMU: dimethylurea

EICA: ethyl isocyanoacetate

EM: enyne metathesis

ERRM: enyne ring-rearrangement metathesis

FI: Fischer indolization

LiHMDS: lithium bis(trimethylsilyl)amide

RCEM: ring-closing enyne metathesis

ROCM: ring-opening cross-metathesis

ROM: ring-opening metathesis

RRM: ring-rearrangement metathesis

TA: tartaric acid

TBAB: tetrabutylammonium bromide

TBAHS: tetrabutyl ammonium hydrogen sulfate

Acknowledgment

S.K. thanks Professors G. Mehta and J. M. Cook for providing an opportunity to work in the polyquinane area during his doctoral and postdoctoral studies, respectively.

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Picrotoxinin:
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Paniculatine:
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Frontalamide A and B:
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Cyclopiamine A and B:
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Spirobacillene B:
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Brevianamide A:
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Berkeleyamide D:
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Spirotryprostatin A:
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Mitomycin C:
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Rocaglamide:
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Kalmanol:
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Meloscine:
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Scandine:
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Epimeloscine:
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Deoxycalyciphylline B:
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Isodaphlongamine H:
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Daphlongamine H:
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Bruceolline J:
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Bruceolline I:
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Longeracinphyllins A:
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Amathaspiramide B:
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Pallidol:
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Spirotryprostatin A and B:
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Pseurotin A:
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Erythroskyrin:
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(–)-Coriolin:
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(+)-Hirsutene:
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Cucumins A–D:
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Pleurotellol:
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Hirsutanol A:
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Hirsutanol E:
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Dichomitol:
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Dendroxine:
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(±)-Cameroonanol, isocomene, silphinene, (–)-silphiperfol-6-ene, modhephen-2-ene and modhephenol:
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Laurenene:
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Pentalenene:
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Cantabrenonic acid:
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Conidiogenol, conidiogenone and conidiogenone B:
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(–)-Acutumine:
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Retigeranic acids A and B:
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Spiroindimicin B, C and D:
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For linear triquinanes:
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Merrilactone A:
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Anislactones A:
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Publication History

Received: 31 August 2020

Accepted after revision: 12 October 2020

Accepted Manuscript online:
12 October 2020

Article published online:
18 November 2020