Synthesis of cyclic proline-containing peptides via ring-closing metathesis

[reaction: see text] Several dienes embedded in di- and tripeptides which incorporate proline have been prepared and subjected to ring-closing metathesis. Bicyclic peptides of well-defined amide geometry and of varying ring sizes were prepared. Several limitations of the cyclization step were revealed.     

Synthesis of 2,6-dideoxysugars via ring-closing olefinic metathesis

[formula: see text] Grubbs' RuCl2 (=CHPh)(PCy3)2 (catalyst 1) and RuCl2(=CHPh)(PCy3)(IMess) (catalyst 2) complexes have been successfully utilized in the construction of beta,gamma-unsaturated delta-lactones containing various substitution patterns of methyl groups. Asymmetric dihydroxylation followed by reduction leads to 3,4-cis-dihydroxy-2,6-dideoxypyranoses, which have proven to play very important biological roles as key components of natural products.     

Synthesis of sialic acids via desymmetrization by ring-closing metathesis

Formal total syntheses of the naturally occurring deaminated sialic acids KDN (2), a potential oncofetal antigen, and N-acetylneuraminic acid (Neu5Ac, 1), the most naturally abundant sialic acid, have been accomplished in 46% and 9.3% overall yield, respectively, via a novel ketalization/ring-closing metathesis sequence. The rapid introduction of all oxygen and nitrogen functionality in a completely stereocontrolled manner exploited a rigid 6,8-dioxabicyclo[3.2.1]oct-2-ene template. The 2,7-anhydro-KDN derivative 40 served as an advanced intermediate in each of the two syntheses.     

Synthesis of bridged azabicyclic structures via ring-closing olefin metathesis

A new strategy for the facile synthesis of azabicyclo[m.n.1]alkenes (m = 3-5; n = 3, 2) has been developed that involves the ring-closing metathesis (RCM) reaction of cis-2,6-dialkenyl-N-acyl piperidine derivatives. The requisite 2,6-dialkenylpiperidines may be readily prepared in six steps starting from glutarimide (11) or three steps from 4-methoxypyridine (25). In one example that establishes the practical utility of the procedure, the functionalized 8-azabicyclo[3.2.1]octane 32, which is a potential intermediate for the syntheses of various tropane alkaloids, was prepared. Additionally, a new route for the construction of the bridged tetrahydro-beta-carboline ring system 5 has been developed that features the ring-closing metathesis of the enyne 45 to construct the bridging ring in 46. This concise route to 46 also features a potentially general and useful procedure for the one-step preparation of a terminal alkyne from an ester function. Selective oxidation of the vinyl group in 46 afforded the unsaturated aldehyde 47, which may serve as a useful intermediate in syntheses of several Sarpagine alkaloids.     

Synthesis of resorcinylic macrocycles related to radicicol via ring-closing metathesis

Novel resorcinylic macrolides, for example, 17, 24, were prepared via ring-closing metathesis as analogues of the HSP90 inhibitor radicicol.     

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.     

Synthesis of cyclic sulfamoyl carbamates and ureas via ring-closing metathesis

Synthetic routes to a diverse set of cyclic sulfamoyl carbamates and ureas are reported. These routes utilize 3-component coupling, Mitsunobu alkylation, and ring-closing metathesis using the second-generation Grubbs catalyst to achieve the synthesis of the target S-heterocyclic compounds. Cyclic S-heterocycles ranging from 9- to 11-membered rings have been obtained.     

Synthesis of thromboxane B2 via ketalization/ring-closing metathesis

Total synthesis of thromboxane B2 using intermolecular ketalization followed by ring-closing metathesis is reported. Other key steps include a Sharpless asymmetric epoxidation to form an oxirane on the endo face of the bicyclic acetal, epoxide opening using lithioacetonitrile, an allylic alcohol 1,3-transposition, and Mitsunobu lactonization.     

Synthesis of (+)-didemniserinolipid B via ketalization/ring-closing metathesis

A modular synthesis of didemniserinolipid B is reported. Central to this synthesis was the use of a ketalization/ring-closing metathesis (K/RCM) strategy to establish the 6,8-dioxabicyclo[3.2.1]octane core. The C10 axial alcohol was established via a selective epoxidation, followed by reductive trans-diaxial epoxide opening. The serinol and unsaturated ester side chains were introduced by a Williamson etherification and cross metathesis, respectively.     

Synthesis of Δ-pyrrolines and Δ-tetrahydropyridines via microwave-accelerated ring-closing metathesis

Microwave irradiation effects ring-closing metathesis of electron-deficient and sterically conjested double bonds with a drastic reduction in reaction time and reduced catalyst loading.     

Synthesis of substituted 1-benzazepin-2-ones via ring-closing olefin metathesis

The 1-benzazepin-2-one ring system is an important structural feature of marketed drugs, clinical candidates, and other bioactive molecules. We have developed a new benzazepinone synthesis that employs ring-closing olefin metathesis as a key step. This route provides efficient access to substituted benzazepinones that are difficult to synthesize via existing procedures.     

Synthesis of ‘inside-outside’ medium-sized rings via ring-closing metathesis

Functionalized and unfunctionalized dienes were synthesized from lactones 7 and 6, respectively, which were subjected to ring-closing metathesis (RCM) using Grubbs’ catalysts. These dienes provide a systematic study of the stereochemical requirements for efficient cyclization. Moreover, it has been established that, within a uniquely defined oxabicyclo[3.3.0]octane template, medium sized rings bearing an ‘in-out’ intrabridgehead stereochemical relationship can been synthesized in good yield.     

Formation of macrocycles via ring-closing olefin metathesis

The enhanced metathesis activity of 1,3-dimesityl-4,5-dihydroimidazole-2-ylidene ruthenium carbene catalyst 3 significantly increases the feasibility of synthesizing macrocyclic compounds. Catalyst 3 exhibits sufficient activity in RCM to dimerize alpha,beta-unsaturated ester substrates and afford the corresponding head-to-tail (E,E)-dimeric (and trimeric) macrocycles. The dimerization appears to be under thermodynamic control with the product mixture dependent not only on the electronic and steric nature of the substrate but also on concentration.     

Synthesis of spirocyclic thiazolidinediones using ring-closing metathesis and one-pot sequential ring-closing/cross metathesis

A novel synthetic route to spirocyclic thiazolidinediones is reported by utilizing ring-closing metathesis (RCM). A selective cross metathesis (CM) of N-allyl azaspiro derivatives with different olefins has been demonstrated to prepare substituted azaspiro-[4.4]nonenediones. The X-ray crystal structure of a spirocyclic thiazolidinedione dimer is described, which has been prepared in two steps from thiazolidinedione using a one-pot sequential ring-closing and self metathesis. Cross metathesis proceeds smoothly with both electron rich and poor olefins. The symmetrical bis-thiazolidinedione spirocyclic system can be used as CM coupling partner with olefins. One-pot sequential RCM-CM has been developed for the synthesis of substituted spirocyclic compounds. The methodology allows a quick access to thia-azaspiro-[4.4]nonene and -[4.5]decene-dione ring systems from readily available starting materials which are not otherwise accessible.     

Diversity-oriented approach to spirocycles via ring-closing metathesis

We have demonstrated a simple and an efficient method for the synthesis of spirocycles starting with inexpensive and commercially available carbonyl compounds. Various spirocycles involving spiropropellane derivative have been assembled via ring-closing metathesis with the aid of Grubbs’ first generation catalyst.     

Synthesis of vinyl fluorides by ring-closing metathesis

The first ring-closing olefin metatheses of alkenyl α-fluoroacrylamides or acrylates incorporating a fluorinated double bond are reported. Several N-benzyl-N-alkenyl-α-fluoroacrylamides were cyclized in the presence of 2 mol % of Grubbs II catalyst at room temperature to form an unsaturated γ-lactam, and at 80 °C to form the corresponding δ-lactams bearing a fluoro vinyl moiety. At elevated temperature, cyclization of an N-methallyl 2-fluoroacrylamide to form a fluorinated, tetrasubstituted double bond was achieved. Similarly, 3-fluorocoumarin was prepared from (2-vinylphenyl)-α-fluoroacrylate.     

Synthesis of cyclic sulfones by ring-closing metathesis

A general and highly efficient synthesis of cyclic sulfones based on ring-closing metathesis has been developed. The synthetic utility of the resulting cyclic sulfones was demonstrated by their participation in stereoselective Diels-Alder reactions and transformation to cyclic dienes by the Ramberg-B?cklund reaction.     

Synthesis of cyclic peptidosulfonamides by ring-closing metathesis

N-Protected beta-aminoethanesulfonyl chlorides (2a-e) were used in the preparation of sulfonamides 4, 8, 11a-c, and 15. Ring-closing metathesis of sulfonamides 4 and 8 did not lead to the expected nine-membered cyclic peptidosulfonamides. In contrast, the allylated peptidosulfonamides 11a-c and 15 turned out to be suitable precursor systems for ring-closing metathesis using second-generation Grubbs catalyst and nine-membered cyclic peptidosulfonamides were obtained in 47-60% yields. The possibility for incorporation of these cyclic peptidosulfonamides into a peptide sequence was illustrated by the incorporation of an amino acid on the "S"- or "N"-terminus leading to 16 and 18-20, respectively. A model of cyclic peptidosulfonamide 16 hints at an extended-like structure.     

Synthesis of 4,4-difluoroglycosides using ring-closing metathesis

4-Deoxy-4,4-difluoro-glycosides have been synthesised for the first time via a direct sequence involving ring-closing metathesis and indium-mediated difluoroallylation with 1-bromo-1,1-difluoropropene in water. Two protecting group strategies were explored, one to allow protection of the primary C-6 hydroxyl group throughout the sequence, while the second was intended to allow deprotection after RCM and before dihydroxylation. The benzyl ether could be used in the first role, and pivaloyl is effective in the second. Dihydroxylations were highly stereoselective and controlled by the orientation of the glycosidic C-O bond.