Application of ring-closing metathesis to the synthesis of 19-functionalized derivatives of 1alpha-hydroxyvitamin D3

[STRUCTURE: SEE TEXT] The synthesis of the 19-functionalized derivative of vitamin D3 based on ring-closing metathesis (RCM) is presented.     

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 cyclitols via ring-closing metathesis

A convenient synthesis of enantiomerically pure and differentially protected l-chiro- and myo-inositols as well as conduritols B and F from 2,3,4-tri-O-benzyl-d-xylopyranose via ring-closing metathesis is reported. The facile synthesis of conduritol B constitutes a short formal synthesis of (−)-cyclophellitol.     

seco-C/D ring analogues of ergot alkaloids. Synthesis via intramolecular Heck and ring-closing metathesis reactions

[reaction: see text] Intramolecular Heck and ring-closing metathesis reactions on key intermediates 10 and 15, respectively, provide efficient entries into seco-C/D ring analogues of Ergot alkaloids 12 and 16, compounds of potential synthetic and biological interest.     

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 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 cyclic phosphonate analogues of (lyso)phosphatidic acid using a ring-closing metathesis reaction

We describe a versatile and efficient method for the preparation of acyloxy-substituted six-membered cyclic phosphonates using the ring-closing metathesis. After closure, the key cyclic phosphonate intermediate was dihydroxylated and converted to a new class of conformationally constrained PA and LPA analogues. The oleoyloxy-substituted cyclic phosphonate 4 had unique receptor-selective properties as a ligand, showing partial activation of the LPA2 GPCR and weak antagonism of the LPA1 GPCR.     

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 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.     

Concise formal synthesis of (-)-peduncularine via ring-closing metathesis

[reaction: see text] A synthesis of the 6-aza[3.2.1]bicyclooctene (-)-2 has been completed by a short sequence of reactions that required only six operations from (S)-malic acid and featured a novel ring-closing metathesis to form the bridged bicyclic ring. Because 2 was previously converted into (-)-peduncularine (1), its preparation constitutes a formal enantioselective synthesis of 1.     

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 the bryostatin 1 northern hemisphere (C1-C16) via desymmetrization by ketalization/ring-closing metathesis

[reaction: see text] Synthesis of the northern hemisphere (C1-C16) of bryostatin 1, a potent anticancer agent, has been accomplished in 14 steps and 11% overall yield via desymmetrization by ketalization/ring-closing metathesis. A 2,9-dioxabicyclo[3.3.1]nonane template facilitated stereoselective A-ring functionalization, while an efficient hetero-Diels-Alder reaction was used to elaborate the B-ring.     

Alpha-phosphono lactone analogues of farnesyl pyrophosphate: an asymmetric synthesis via ring-closing metathesis

An alpha-phosphono lactone derivative of farnesol has been prepared, in both racemic and nonracemic forms, to provide a new type of farnesyl pyrophosphate analogue. Attempted preparation of the racemic alpha-phosphono lactone through rearrangement of a vinyl phosphate derived from the parent lactone resulted in both rearrangement and lactone ring opening, revealing that the farnesyl lactone was not stable to the excess of strong base required for the rearrangement. A procedure for C-P bond formation based on generation of the lactone enolate, reaction with a P(III) reagent, and oxidation was successful in providing the racemic alpha-phosphono lactone, in part, because only 1 equiv of strong base was required. The same strategy for phosphonate synthesis then was applied to the nonracemic farnesyl lactone, prepared through a sequence including allylation of farnesal with a nonracemic borane reagent, reaction of the product alcohol with acryloyl chloride, and formation of an unsaturated lactone through ring-closing metathesis. A similar strategy gave the corresponding racemic alpha-phosphono lactam through a six-step sequence from farnesal.     

Simple thiazocine-2-acetic acid derivatives via ring-closing metathesis

A new protocol for synthesis of 2-heterocylylacetic acid derivatives involving conjugate addition of allyl mercaptan to an acrylate containing a tethered olefinic site followed by RCM (ring-closing metathesis) is described. In this series, sulfanyl derivatives were unreactive, while sulfoxide and sulfone analogues provided the corresponding thiazocines in fair to excellent yields. Use of the sulfoxide oxidation state as a protecting group for sulfides inert to RCM is demonstrated also. Thus, oxidation of sulfide 9 [N-allyl-N-[2-(allylthio)-4-(1H-indol-1-yl)-4-oxobutyl]-4-methylbenzenesulfonamide] followed by cyclization yielded the corresponding thiazocine sulfoxide 12. Deprotection (deoxygenation) of 12 was accomplished using Lawesson's reagent, producing 1-[[4-[4-(methylphenyl)sulfonyl]-3,4,5,8-tetrahydro-2H-1,4-thiazocin-2-yl]acetyl]-1H-indole (21) in 67% unoptimized yield.     

Total synthesis of (-)-aspidospermine via diastereoselective ring-closing olefin metathesis

An enantiocontrolled total synthesis of (-)-aspidospermine has been achieved. The key element of the strategy is the diastereoselective construction of the quaternary stereogenic center employing 1,4-asymmetric induction during the ring-closing olefin metathesis.