Relay Ring-closing Metathesis Research Articles

A relay ring-closing metathesis/Diels-Alder approach to sugar-derived pluramycin-hybrids.

Herein, we present a general approach for synthesizing pluramycin hybrids, which are analogous to the pluramycinone carbocyclic skeleton. This method involves a sequence of relay ring-closing enyne metathesis, Diels-Alder and oxidative aromatization reactions to synthesize pluramycinone-sugar hybrids. As part of our ongoing research, we have successfully synthesized two pluramycin hybrid analogues by carefully monitoring the late-stage oxidative aromatization steps, which depend on the stereo-orientation of the Diels-Alder cycloadduct at the C-4 center. The undesired ring-opening product can also serve as a C-glycoside analog, providing a versatile convergent route to access both types of hybrids and highlighting the significance of this strategy.

Convergent synthesis of the [5-7-6-3] tetracyclic core of premyrsinane diterpenes.

The [5-7-6-3] tetracyclic core of premyrsinane diterpenes was convergently synthesized via the stereoselective three-component coupling of a 2-propenyl unit, an enone, and an aldehyde, followed by the relay ring-closing metathesis with conformation control of the substrate to construct the 7-membered ring.

Relay ring-closing metathesis strategies towards the synthesis of the ABC tricycle of Taxol

Two synthetic routes towards the ABC tricycle of Taxol are presented. They both involve a relay ring-closing metathesis reaction to make the central B ring in a convergent fashion. In the first approach, the extender arm is positioned on the A ring, and the C ring bears the relay tether in the second route. Metathesis precursors with diverse extender arms were efficiently synthesised; unfortunately, the crucial metathesis reactions failed to deliver the target compounds in all cases.

Stereoselective Synthesis of the I-L Fragment of the Pacific Ciguatoxins.

The I–L ring system found in all the Pacific ciguatoxins has been prepared from a tricyclic precursor in a highly stereoselective manner. Subtle differences in the reactivity of the enones present in the seven- and eight-membered rings of the tricyclic ether starting material have been exploited to allow selective protection of the enone in the eight-membered ring. Subsequent distereoselective allylation of the seven-membered ring has been accomplished by a palladium-mediated Tsuji-Trost reaction. The K-ring methyl and hydroxyl groups have been installed in a highly stereoselective manner by sequential conjugate reduction and enolate oxidation reactions. Ring L has been constructed by a use of a novel relay ring-closing metathesis reaction to complete the tetracyclic framework, which possesses the functionality necessary for elaboration of rings I and L and the introduction of ring M.

Unintended Formation of a 26-Membered Cycle in the Course of a Novel Approach to Myricanol, a Strained [7,0]-Metacyclophane

A convergent approach for the synthesis of (±)-myricanol, a strained diarylheptanoid isolated from Myricacae, was undertaken using a Suzuki–Miyaura coupling followed by a ring-closing metathesis (RCM). Herein, we report the unintentional formation of a 26-membered macrocycle as RCM product resulting from a head-to-tail dimerization of the seco-precursor, even in relay ring-closing metathesis (RRCM) conditions.

Enantioselective Construction of Functionalized Cyclopentanes by a Relay Ring-Closing Metathesis and Chiral Amine (Thio)urea-Promoted Michael Addition

A relay strategy is described that permits ring-closing metathesis and bifunctional chiral amine (thio)urea-catalyzed Michael­ addition reactions to proceed in a one-pot fashion. The process offers an alternative approach to the synthesis of structurally diverse chiral cyclopentanes in good yields and good enantioselectivities.

Concise total syntheses of heliannuols B and D

Concise and efficient enantioselective total syntheses of heliannuols B and D have been accomplished using chirality transfer through a Lewis acid-promoted Claisen rearrangement for the construction of the C7 tertiary stereogenic center and a relay ring-closing metathesis for assembling the dihydrobenzo[b]oxepine backbone of the natural products as the key steps.

Enabling Access to Diverse Bioactive Molecules Through Enyne Metathesis Concepts

This paper surveys recent advances in valorization of transition-metal-catalyzed enyne metathesis as key events in the total synthesis of naturally occurring compounds of biological and medicinal importance. Special attention is devoted to methodologies based on dienyne ring-closing metathesis (RCM) applied in tandem and sequential processes, on relay ring-closing metathesis (RRCM), ringrearrangement metathesis (RRM), enyne cross-metathesis (CM) and enyne skeletal bond reorganization, all proceeding under metalcarbenes (Ru or Mo alkylidenes) or metal-salts (Pd or Pt) catalysis. The high potential of these procedures in constructing versatile scaffolds as essential structural cores of a diversity of bioactive natural products is highlighted. Inventive functionalizations by nonmetathesis transformations intervening in the total synthesis of the targeted natural compounds, prior to (Michael addition, Wittig olefination, allylation etc.) or after (Diels-Alder cycloaddion, Heck and Suzuki-Miyaura reactions, Dess-Martin oxidation, dihydroxylation, epoxidation etc.) the pivotal metathesis step have also been included.

Total Synthesis of Stemaphylline N‐Oxide and Related C9a‐Epimeric Analogues

Winning the relay: The first total synthesis of stemaphylline N-oxide has been completed utilizing a bistandem relay ring-closing-metathesis (RRCM) strategy, necessitated by the conformation of the requisite tetraene. This effort also gave unnatural 9a-epi-stemaphylline and 9a-epi-stemaphylline N-oxide.

Stereoselective Total Syntheses of (−)‐Flueggine A and (+)‐Virosaine B

Convergent approach: the total syntheses of (-)-flueggine A and (+)-virosaine B have been accomplished in a concise and convergent manner. Key steps in these approaches were relay ring-closing metathesis reactions for rapid construction of the key intermediates, and 1,3-dipolar cycloaddition reactions for the formation of the natural products.

A Formal Synthesis of (−)-Englerin A by Relay Ring Closing Metathesis and Transannular Etherification

A bicyclization approach to englerin A has culminated in a formal asymmetric total synthesis. Key transformations in the 10-step sequence are a regiospecific epoxide opening and a relay ene-yne-ene metathesis that converts linear substrates specifically to Δ(4,6)-guaiadiene-9,10 diol derivatives. Regiospecific functionalization of the diene moiety installs the oxygen bridge required for the englerin tricyclic core.

Total Synthesis of Penostatin B

The first total synthesis of penostatin B has been accomplished by using a highly diastereoselective Pauson-Khand reaction and an efficient relay ring-closing metathesis for the construction of the basic carbon skeleton of the natural product as the key steps.

Allylmalonate as an Activator Subunit for the Initiation of Relay Ring-Closing Metathesis Reactions

Passing the baton: The relay ring-closing metathesis (RRCM) reaction of complex polyenes 1 has been studied. Several relay subunits (T) were examined and many did not sufficiently activate the RRCM. An allylmalonate-containing relay subunit solved this problem, and efficiently lead to the diene 2. TIPS=triisopropylsilyl.

Synthesis of the Cyclohexane Core of Phomactins and a New Route to the Bicyclo[9.3.1]pentadecane Diterpenoid Skeleton

Conjugate reduction of an enone accompanied by in situ intramolecular aldol condensation was used to construct the tetrasubstituted cyclohexane nucleus of phomactins. Subsequent relay ring-closing metathesis completed the nine-membered ansa bridge of the diterpenoid framework.

Total Synthesis of (−)-Callipeltoside A

A total synthesis of (-)-callipeltoside A (1) has been achieved. The core macrocycle was made via a dual macrolactonization/pyran hemiketal formation reaction, developed to circumvent issues related to the reversible nature of acylketene formation from β-keto lactone substrates. Initial approaches to the core of the natural product that revolved around ring-closing metathesis (RCM) and relay ring-closing metathesis (RRCM) reactions are also described.

Total synthesis of peloruside A through kinetic lactonization and relay ring-closing metathesis cyclization reactions.

A convergent total synthesis of peloruside A (1) is described. The key strategic features are a diastereoselective lactonization to generate a C5-C9 valerolactone from the C2-symmetric ketone 4, which comprises C1–C9 of 1, and a relay ring closing metathesis (RRCM) reaction to produce a dehydrovalerolactone 20, which embodies C13–C19. A new isomer of 1, the valerolactone iso-peloruside A (iso-1), was identified.

Model studies for the stereoselective construction of the BC-ring of armatol F based on Ireland-Claisen rearrangement and relay ring-closing olefin metathesis

Armatol F, isolated from the red alga Chondria armata as a polyether triterpene, has a fused tricyclic ether moiety (BCD-ring) with an unusual cis ring junction at C18–C19 between the C- and D-rings. En route to the total synthesis of armatol F, the stereoselective construction of the C18 and C19 stereocenters by Ireland-Claisen rearrangement and the formation of the C-ring by relay ring-closing olefin metathesis were established through the synthesis of monocyclic (C-ring) and bicyclic (BC-ring) model compounds.

A convergent approach toward phoslactomycins and leustroducsins

Synthetic studies devoted to the development of a convergent approach toward phoslactomycins and leustroducsins, a family of natural products inhibitors of serine/threonine phosphatase 2A, are reported. A formal synthesis of phoslactomycin B was achieved in which the key steps are a [2,3]-Wittig rearrangement to control the C4 and C5 stereocenters, a diastereoselective addition of an acetylenic Grignard reagent to an α-alkoxy ketone to create the C8 tertiary alcohol, and a relay ring-closing metathesis to construct the α,β-unsaturated δ-lactone. In this approach, all the stereocenters originate, either directly or indirectly, from catalytic enantioselective reductions of acetylenic ketones.

Trisubstituted cyclooctene synthesis at the limits of relay ring-closing metathesis: a racemic difluorinated analogue of fucose

A telescoped sequence based on metallated enol acetal chemistry allowed the efficient delivery of a ring-closing metathesis (RCM) precursor, which was used to form a cyclooctenone product with a trisubstituted alkenyl group in moderate yield, though a high loading of second generation Grubbs' pre-catalyst was required. A relay RCM (RRCM) precursor was synthesised to deliver the key alkylidene at a higher rate; the catalyst loading required was high, and increasing the reaction temperature simply resulted in the loss of the cyclising alkylidene by a non-productive cross-metathesis pathway. We were forced to use high dilution conditions to suppress the unwanted CM and secure the cyclooctenone product. The cyclooctenone product could be progressed to analogues of fucose and 6-deoxyidose by UpJohn dihydroxylation.

Solid-phase based total synthesis of Jasplakinolide by ring-closing metathesis

The study of classical ring-closing metathesis and relay ring-closing metathesis in a total synthesis of Jasplakinolide and its desbromo analog is described.