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.     

Glycomimetic building blocks: a divergent synthesis of epimers of shikimic acid

A divergent synthesis of (-)-4-epi-shikimic acid was developed. This route features a one-pot zinc-mediated reductive ring opening of an arabinofuranose followed by a Barbier reaction and culminates in a ring-closing metathesis. Functionalization of (-)-4-epi-shikimic acid via conjugate addition of a thiol occurs in high diastereoselectivity to afford a product with the features of fucosylated glycans.     

Total synthesis of (+)-laurencin: an asymmetric alkylation-ring-closing metathesis approach to medium ring ethers

[formula: see text] The enantioselective total synthesis of (+)-laurencin 1 is achieved in 18 steps from (S)-(+)-4-benzyl-3-benzyloxyacetyl-2-oxazolidinone. The key steps in this synthesis are an asymmetric glycolate alkylation leading to acyl oxazolidinone 2 and a subsequent ring-closing olefin metathesis to construct the oxocene core of 1. The approach to medium ring ethers utilized in this synthesis provides a general and efficient route to the cyclic core of other marine natural products.     

Asymmetric synthesis of (-)-swainsonine, (+)-1,2-di-epi-swainsonine,and (+)-1,2,8-tri-epi-swainsonine

The asymmetric synthesis of (-)-swainsonine via a nonchiral pool route that involves the Sharpless epoxidation to induce chirality is reported. The key steps involve vinyl epoxide aminolysis, ring-closing metathesis, and intramolecular N-alkylation to prepare the indolizidine ring and a highly diastereoselective cis-dihydroxylation using AD-mix-alpha. This synthetic strategy also allowed for the diastereoselective synthesis of (+)-1,2-di-epi-swainsonine and (+)-1,2,8-tri-epi-swainsonine.     

Synthesis of Berkeleylactone A by Ring-Closing Alkyne Metathesis

A new route to the macrolactone antibiotic berkeleylactone A was developed. As a key step, a ring-closing alkyne metathesis (RCAM) of an ester substrate featuring 1-propynyl termini was used. The carboxylic part of the substrate was easily assembled using alkyne chemistry, like carboxylation of a diyne followed by isomerization of the ynoate section to a dienoate and dihydroxylation of the 4,5-double bond. The synthesis of the alcohol part of the ester started with opening of (R)-propylene oxide with an acetylide and was followed by two triple bond migrations. After successful RCAM which formed the C8−C9 bond, the triple bond was selectively hydrogenated to the corresponding alkene before the 4,5-diol was oxidized to the 5-hydroxy-4-oxo derivative. At this stage, the thioether was formed and the 8,9-double bond reduced. We also prepared the 8,9-didehydro analog of berkeleylactone A. However, it turned out that its antimicrobial activity was slightly reduced.     

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.     

A simple and efficient stereoselective synthesis of (−)-cleistenolide

A simple and straightforward stereoselective synthesis of α,β-unsaturated δ-lactone, (?)-cleistenolide has been accomplished in 10 steps in an overall yield of 19%, starting from inexpensive and commercially available starting materials, respectively. This linear synthesis utilizes Sharpless asymmetric dihydroxylation, sulfur ylide mediated epoxide opening followed by ring-closing metathesis (RCM) for the formation of six-membered lactone ring as the key step sequence.     

A concise and efficient synthesis of (-)-allosamizoline

A regio- and stereocontrolled total synthesis of (-)-allosamizoline is described. The key steps for this synthesis are ring-closing metathesis to form the cyclopentene core, halocyclization to afford the oxazoline ring, and finally stereoselective alkene radical addition followed by an alkene isomerization reaction to install the hydroxymethyl group. (-)-Allosamizoline was prepared in a total of 13 steps and 22% overall yield.     

A convergent synthesis of the tricyclic core of the dictyosphaeric acids

The first synthetic route to the tricyclic core of the dictyosphaeric acids has been established starting from readily available (S)-(-)-4-(tert-butyldimethylsilyloxy)cyclohexenone and involving 9 steps, including a ring-closing metathesis to produce a 13-membered macrolactone, and a doubly tethered intramolecular Michael addition.     

A concise enantioselective entry to the synthesis of deoxy-azasugars

[reaction: see text] A concise enantioselective preparation of oxazolidinylpiperidine 4, a key intermediate in the synthesis of glycosidase inhibitors such as 1-deoxymannojirimycin or 1-deoxygalactostatin, has been developed. Sharpless catalytic asymmetric epoxidation of (E)-2,4-pentadienol followed by treatment with allyl isocyanate afforded epoxy carbamate 8. Regioselective intramolecular ring opening promoted by sodium bis(trimethylsilyl)amide and ring-closing metathesis provided the bicyclic intermediate 4 in high enantiomeric purity. The four-step sequence takes place in 51% overall yield.     

Facile asymmetric synthesis of the core nuclei of xanthanolides,guaianolides, and eudesmanolides

[reaction: see text] Bicyclic and tricyclic gamma-butyrolactones with 5,7-, 5,6,5-, 5,6,6-, or 5,7,5-fused ring systems, being found in xanthanolides, eudesmanolides, and guaianolides, were readily synthesized from methyl furan-2-carboxylic acid. Key steps were a copper(I)-catalyzed asymmetric cyclopropanation, Sakurai allylations, intramolecular ene reactions, and ring-closing metathesis reactions.     

Asymmetric total syntheses of two phlegmarine-type alkaloids, lycoposerramines-V and -W, newly isolated from Lycopodium serratum

Two new Phlegmarine-type alkaloids, lycoposerramines-V and -W, were isolated from Lycopodium serratum, and their structures including the absolute configuration were established by asymmetric total synthesis involving such key steps as Johnson-Claisen rearrangement, asymmetric allylation, and ring-closing metathesis (RCM)- or SmI(2)-mediated stereoselective piperidine ring construction.     

Phosphate tether-mediated approach to the formal total synthesis of (-)-salicylihalamides A and B

A concise formal synthesis of the cytotoxic macrolides (-)-salicylihalamides A and B is reported. Key features of the synthetic strategy include a chemoselective hydroboration, highly regio- and diastereoselective methyl cuprate addition, Pd-catalyzed formate reduction, and an E-selective ring-closing metathesis to construct the 12-membered macrocycle subunit. Overall, two routes have been developed from a readily prepared bicyclic phosphate (4 steps), a 13-step route and a more efficient 9-step sequence relying on regioselective esterification of a key diol.     

An enantioselective entry to cis-perhydroisoquinolines

An enantioselective route to cis-perhydroisoquinolines, involving a cyclocondensation reaction of (R)-phenylglycinol with a racemic oxoester, a stereoselective conjugate addition to an unsaturated bicyclic lactam, and the closure of the carbocyclic ring by a ring-closing metathesis as the key steps is reported. This route allows the preparation of 3-cyano derivatives as well as cis-octahydroisoquinolines bearing a quaternary center at the C4-position. [reaction: see text]     

Total synthesis of the terpenoid buddledone A: 11-membered ring-closing metathesis

The first total synthesis of buddledone A was accomplished in seven steps from methyl ethyl ketone (MEK). The key step in the sequence featured an 11-membered ring formation by ring-closing metathesis.     

Synthesis studies on the Melodinus alkaloid meloscine

The pentacyclic Melodinus alkaloid (±)-meloscine was synthesized in 19 chemical steps from 2-bromobenzaldehyde through a route featuring an allenyl azide cyclization cascade to deliver the core azabicyclo[3.3.0]octane substructure. Peripheral functionalization of this core included a Tollens-type aldol condensation to set the quaternary center at C(20) and a diastereoselective ring-closing metathesis to forge the tetrahydropyridine ring.     

Synthesis of ovalicin starting from D-mannose

[reaction: see text] A new synthesis of epoxyketone 22 is described that is a key intermediate in Barton's synthesis of ovalicin (2), a powerful anti-angiogenetic inhibitor. The key process for the construction of 22 was ring-closing metathesis of olefins 11 and 12 obtained from 2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose (4) and regioselective desilylation of tri-TES ether 19. Furthermore, an alternative stereoselective route from 22 into 2 has also been developed, and the overall yield of 2 from 4 was 10.0%.     

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.     

Catalyst-controlled inverse-electron-demand hetero-Diels-Alder reactions in the enantio- and diastereoselective synthesis of iridoid natural products

[reaction: see text] Iridoid natural products 1-4 are accessed stereoselectively by means of tridentate (Schiff base)Cr(III)-catalyzed hetero-Diels-Alder reactions between ethyl vinyl ether and enantioenriched 5-methyl-1-cyclopentene-1-carboxaldehyde. An efficient route to the aldehyde from citronellal is afforded by the ring-closing metathesis reaction.     

Convergent synthesis of the HIJKLM ring system of ciguatoxin CTX3C

The HIJKLM ring system of ciguatoxin CTX3C was synthesized in a convergent manner. The key steps were a conjugate addition/alkylation sequence, spiroacetalization, intramolecular allylation, ring-closing metathesis, and hydrogenation to form the 36-α-methyl substituent.