Recent applications of ring-closing metathesis in the synthesis of lactams and macrolactams

Lactams are an important class of compounds owing to their presence in numerous biologically active molecules of natural and unnatural nature. They are also highly versatile intermediates that can be elaborated into interesting compounds for potential use in organic and medicinal chemistry endeavors. In this feature article, the reader will be given a background to olefin metathesis followed by concise discussions (with selected examples) to report recent applications of ring-closing metathesis to form lactams and macrolactams from acyclic diene precursors, an area which continues to deposit attractive applications in the chemical literature en route or in the final step to the target molecules.     

Application of tandem Ugi multi-component reaction/ring closing metathesis to the synthesis of a conformationally restricted cyclic pentapeptide

A conformationally restricted cyclic pentapeptide, containing an unsaturated 9-membered lactam as a semi-rigid scaffold, was prepared in a very convergent manner, through tandem Ugi reaction/ring closing metathesis.     

Stereoselective synthesis of eight-membered cyclic ethers by tandem Nicholas reaction/ring-closing metathesis: a short synthesis of (+)-cis-Lauthisan

[STRUCTURE: SEE TEXT] Cis-2,8-disubstituted oxocanes and the parent unsaturated precursors were prepared from the corresponding Co2(CO)6-cycloalkynic ethers. Key steps in such synthesis were the ether linkage formation by intermolecular Nicholas reaction, RCM of the suitable acyclic dienyl ether and montmorillonite K-10 induced isomerization of the complexed cycloalkyne. A short synthesis of (+)-cis-lauthisan taking advantage of the developed methodology is described.     

Concise total synthesis of (-)-muricatacin by tandem ring-closing/cross metathesis

A strategy for the synthesis of chiral 5-(1-hydroxyalk-2-enyl)-5H-furan-2-ones and its application to the total synthesis of (-)-muricatacin, in four steps and 37% overall yield from (R,R)-hexa-1,5-diene-3,4-diol, are described. The key synthetic step in this approach is a highly regioselective and stereoselective tandem ring-closing/cross metathesis reaction in which both lactone formation and alkyl chain extension are accomplished in an efficient one-pot process.     

Carbohydrate carbocyclization by a zinc-mediated tandem reaction and ring-closing enyne metathesis

Methyl 5-deoxy-5-iodo-pentofuranosides are reductively ring-opened and propargylated in a tandem fashion in the presence of zinc. The 1,7-enynes thus obtained are subjected to ring-closing enyne metathesis with catalyst B to produce functionalized 1-vinyl cyclohexenes. By adding BnNH(2) to the tandem reaction, an amino group can be introduced in the 1,7-enyne products. Addition of 2-TMS-ethynylcerium(III) chloride after the reductive ring-opening produces the corresponding 1,6-enynes. Further annulation of the product 1,3-dienes can be achieved through a Diels-Alder reaction with good control of stereochemistry. These procedures constitute efficient methods for rapid carbocyclization and annulation of carbohydrates to produce a variety of functionalized five- and six-membered ring systems.     

Role of the gem-difluoro moiety in the tandem ring-closing metathesis-olefin isomerization: regioselective preparation of unsaturated lactams

Careful selection of the metathesis catalyst, solvent, and reaction conditions allows for the efficient and regioselective synthesis of isomeric fluorinated and nonfluorinated lactam derivatives II and III from precursor amides I through a ring-closing metathesis (RCM) reaction or a tandem RCM-isomerization protocol, respectively. The presence of the gem-difluoro moiety in the starting materials exerts a pivotal effect by directing the isomerization step, making the overall tandem transformation a regioselective process. The scope, limitations, and synthetic usefulness of this protocol are also discussed.     

An efficient synthesis of nitrogen-containing heterocycles via a tandem carbenoid N-H insertion/ring-closing metathesis sequence

A series of five- to eight-membered nitrogen-containing heterocycles were prepared via a general and efficient one-pot, two-component sequence featuring rhodium-catalyzed insertion of a vinyl-substituted α-diazocarbonyls into the N-H bond of a series of tert-butoxycarbonyl-(Boc)-protected amines, followed by ring-closing metathesis catalyzed by ruthenium benzylidene complexes. This methodology allows easy and convenient access to highly functionalized azacycloalkenes in moderate yields and excellent chemoselectivity in a single transformation.     

Synthesis of the tricyclic core of colchicine via a dienyne tandem ring-closing metathesis reaction

The synthesis of the tricyclic framework of colchicine has been achieved using a tandem ring-closing metathesis reaction of dienynes as the key step. In this process, both seven-membered rings B and C were formed in one step. Oxidation of tertiary allylic alcohol derived from the tandem metathesis product furnished an intermediate in the total synthesis of colchicine.     

A convergent synthesis of enantiopure bicyclic scaffolds through multicomponent Ugi reaction

An efficient and convergent Ugi synthesis of enantiomerically pure N-acyl-2,5-disubstituted pyrrolidines was coupled with an appropriate secondary transformation to give two series of bicyclic derivatives, namely hexahydro pyrrolo-oxazocinediones and -diazepinediones.     

Preparation of peptide-like bicyclic lactams via a sequential Ugi reaction--olefin metathesis approach

Bicyclic lactams, suitable for incorporation into conformationally restricted peptide mimics, can be synthesized by using olefinic starting materials for the Ugi multicomponent reaction, setting up an olefin metathesis reaction, that is easily carried out with the Grubbs catalyst. The influence of the different starting materials is evaluated. In addition, the utilization of chiral, nonracemic amines is described.     

Formal synthesis of (+/-)-guanacastepene A: a tandem ring-closing metathesis approach

A concise route to a key intermediate in the total synthesis of guanacastepene A is described. The main features include the simultaneous construction of the seven- and six-membered rings, using a tandem ring-closing metathesis and a stereoselective introduction of the oxygenated function at the C5 position. [reaction: see text]     

Synthesis of biaryl compounds using tandem ruthenium-catalyzed ring-closing metathesis

Tandem ring-closing enyne metathesis (RCEM)/ring-closing olefin metathesis (RCM) of tetraenynes with Grubbs second-generation catalyst, followed by elimination, was found to be a new and efficient synthetic approach to biaryl compounds. A preliminary asymmetric version of this approach, which used homochiral Ru-alkylidene catalysts, is also presented.     

Diastereoselective ring-closing metathesis in the synthesis of dihydropyrans

An investigation into the factors influencing the diastereochemical outcome of the ring-closing metathesis based synthesis of dihydropyrans is presented in this paper. Divinyl carbinols derived from alpha-hydroxy carboxylic acid esters are elaborated to trienes with two diastereotopic vinyl moieties. Depending on the steric demand of the oxo substituent of the divinyl carbinol moiety (either unprotected OH, TBDMS, or benzyl ether) different diastereomers are preferrably formed upon ring-closing metathesis. An extension to diastereoselective double ring-closing metathesis in the formation of spirocycles has also been investigated.     

One-pot three-component tandem metathesis/Diels-Alder reaction

[reaction: see text] A tandem enyne, diene-ene metathesis reaction followed by Diels-Alder reaction accomplished a stereoselective three-component reaction protocol with four stereocenters.     

Formal synthesis of valienamine using ring-closing metathesis

(1R,2S,3S,4R)-2,3,4-Tri-O-benzyl-5-(benzyloxymethyl)-cyclohex-5-ene-1,2,3,4-tetrol, a precursor of the α-glucosidase inhibitor, valienamine, was synthesised in eight steps from tetrabenzyl glucose. The key steps were the selective protection of an open-chain diol, and the formation of the cyclohexene ring by ring-closing metathesis with the trisubstituted olefin of valienamine correctly in place.     

Sequential ring-closing metathesis and silicon-assisted cross-coupling reactions: stereocontrolled synthesis of highly substituted unsaturated alcohols

A sequential ring-closing metathesis/silicon-assisted cross-coupling sequence has been developed. Alkenyldimethylsilyl ethers of omega-unsaturated alcohols undergo facile ring closure with Schrock's catalyst to afford five-, six-, and seven-membered cycloalkenylsiloxanes bearing substituents on both alkenyl carbons. These siloxanes were highly effective coupling partners with various aryl and alkenyl halides and in the presence of Pd(0) afforded styrenes and dienes in high yield and specificity and with good functional group compatibility.     

A quadruple ring-closing metathesis reaction in the synthesis of bis-spirocyclic compounds: extending the scope of metathesis chemistry

The first example of a quadruple ring-closing metathesis reaction is reported. The reaction of the C2 symmetric octaene 3 afforded bis-spirocyclic compounds in high yield.     

Synthesis of beta-bisabolol by ring-closing olefin metathesis reaction

A ring-closing olefin metathesis is the key step in the synthesis of the beta-bisabolols.     

Selective formation of dihydropyran derivatives by a tandem domino ring-closing metathesis/cross-metathesis

A ring-closing metathesis (RCM)/cross-metathesis (CM) domino reaction has been applied to esters and unsymmetrical ether prepared from 1,5-hexadien-3-ol. For the first time, dihydropyran derivatives have been obtained via a regioselective cyclization. This reaction was performed in high yield and E stereoselectivity.     

Synthesis of novel dinucleosides via tandem cross-metathesis and ring-closing metathesis

Two novel cyclic dinucleosides having two butylene linkers between the 5′-OH and N-3 positions (thereby generating a 24-membered ring) were synthesized from uridine via tandem cross-metathesis and ring-closing metathesis. Selective synthesis of one dinucleoside with a link between the two N-3 atoms and a link between the two 5′-OH groups was achieved.