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.     

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.     

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 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%.     

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.     

Total syntheses of the actin-binding macrolides latrunculin A, B, C, M, S and 16-epi-latrunculin B

The latrunculins are highly selective actin-binding marine natural products and as such play an important role as probe molecules for chemical biology. A short, concise and largely catalysis-based approach to this family of bioactive macrolides is presented. Specifically, the macrocyclic skeletons of the targets were forged by ring-closing alkyne metathesis (RCAM) or enyne-yne metathesis of suitable diyne or enyne-yne precursors, respectively. This transformation was best achieved with the aid of [(tBu)(Me(2)C(6)H(3))N](3)Mo (37) as precatalyst activated in situ with CH(2)Cl(2), as previously described. This catalyst system is strictly chemoselective for the triple bond and does not affect the olefinic sites of the substrates. Moreover, the molybdenum-based catalyst turned out to be broader in scope than the Schrock alkylidyne complex [(tBuO)(3)W[triple chemical bond]CCMe(3)] (38), which afforded cycloalkyne 35 in good yield but failed in closely related cases. The required metathesis precursors were assembled in a highly convergent fashion from three building blocks derived from acetoacetate, cysteine, and (+)-citronellene. The key fragment coupling can either be performed via a titanium aldol reaction or, preferentially, by a sequence involving a Horner-Wadsworth-Emmons olefination followed by a protonation/cyclization/diastereoselective hydration cascade. Iron-catalyzed C--C-bond formations were used to prepare the basic building blocks in an efficient manner. This synthesis blueprint gave access to latrunculin B (2), its naturally occurring 16-epimer 3, as well as the even more potent actin binder latrunculin A (1) in excellent overall yields. Because of the sensitivity of the 1,3-diene motif of the latter, however, the judicious choice of protecting groups and the proper phasing of their cleavage was decisive for the success of the total synthesis. Since latrunculin A and B had previously been converted into latrunculin S, C and M, respectively, formal total syntheses of these congeners have also been achieved. Finally, a previously unknown acid-catalyzed degradation pathway of these bioactive natural products is described. The cysteine-derived ketone 18, the tetrahydropyranyl segment 31 serving as the common synthesis platform for the preparation of all naturally occurring latrunculins, as well as the somewhat strained cycloalkyne 35 formed by the RCAM reaction en route to 2 were characterized by X-ray crystallography.     

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.