Synthesis of 2H-1,5-benzodioxepin and 2,5-dihydro-1,6-benzodioxocin derivatives via ring-closing metathesis reaction

The synthesis of various 2H-1,5-benzodioxepin and 2,5-dihydro-1,6-benzodioxocin derivatives is described. The key step involves the construction of seven- and eight-membered rings via ring-closing metathesis reaction.     

Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis

A family of previously reported ring-closing metathesis (RCM)-derived macrocycles that exhibit potent Grb2 SH2 domain-binding affinity is characterized by stereoselectively-introduced upper ring junctions that bear bicyclic aryl substituents. However, the synthetic complexity of these macrocycles presents a potential limit to their therapeutic application. Therefore, the current study was undertaken to simplify these macrocycles through the use of achiral 4-pentenylamides as ring-forming components. A series of macrocycles (5a-f) was prepared bearing both open and cyclic constructs at the upper ring junction. The Grb2 SH2 domain-binding affinities of these macrocycles varied, with higher affinities being obtained with cyclo-substituents. The most potent analogue (5d) contained a cyclohexyl group and exhibited Grb2 SH2 domain-binding affinity (K(D) = 1.3 nM) that was nearly equal to the parent macrocycle (2), which bore a stereoselectively-introduced naphthylmethyl substituent at the upper ring junction (K(D) = 0.9 nM). The results of this study advance design considerations that should facilitate the development of Grb2 SH2 domain-binding antagonists.     

Ring-closing metathesis as a tool for the efficient preparation of chiral spirocyclic ethers from homoallylic alcohols

The preparation of chiral spirocyclic ethers via allylic etherification/olefin metathesis of homoallylic alcohols is investigated. This reaction sequence transforms the enantiopure substrate alcohols, synthesized by a one-pot asymmetric rhodium-catalyzed conjugate addition/metal-mediated allylation procedure, into the desired spiro ethers with full conversions and in excellent isolated yields. The synthetic sequence provides an efficient means for a rapid construction of functionalized spiro ethers in a stereoselective manner.     

Stereoselective synthesis of bicyclo[4.2.1]nonane skeletons by ring-closing metathesis: a new versatile methodology for the efficient assembly of functionalized cyclooctanoids

[reaction: see text] A new versatile methodology, resulting in a formal three-carbon ring expansion of cyclopentanones, for the efficient assembly of functionalized cyclooctanoids is described. The approach is based on the chemo-, regio-, and stereoselective alpha,gamma-difunctionalization of beta-ketoesters followed by ring-closing metathesis to form functionalized bicyclo[4.2.1]nonanes, precursors of the corresponding cyclooctanes, by selective ring cleavage of the one-carbon-atom bridge.     

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.     

Studies towards the total synthesis of palau'amine. Formation of 4,5-dihydropyrrole-2-carboxylate intermediates by alkene-enamide ring-closing metathesis

A highly functionalized 4,5-dihydropyrrole-2-carboxylate is assembled by alkene-enamide ring-closing metathesis. Subsequent intramolecular azomethine imine dipolar cycloaddition provides a triazacyclopenta[cd]pentalene intermediate of potential use in a total synthesis of palau'amine.     

A novel method for the synthesis of functionalized spirocyclic oxindoles by one-pot tandem reaction of vinyl malononitriles with isatylidene malononitriles

One-pot synthesis of novel spirocyclic oxindoles was achieved via vinylogous Michael addition of vinyl malononitriles on isatin-malononitrile adducts as the key step followed by a sequential tandem reaction.     

Exploratory studies aimed at a synthesis of vinigrol. 2. Attempts to exploit ring-closing metathesis for construction of the central cyclooctane belt

A program directed to the possible adaptation of ring closing metathesis to a total synthesis of vinigrol is described. With a convenient route to intermediates of general type 3 available from a prior investigation, several candidate substrates were prepared. These included the epoxy dienes 10 and 22, the diacetoxy triene 42, and the heavily functionalized cyclohexane 48. The central issue of this approach was to convey a maximum degree of conformational flexibility to these functionalized intermediates, such that the olefinic termini of the side chains could enter into intramolecular carbon-carbon bond formation. In no example was ring closure observed to operate. Instead, the strategically placed pi-bonds were seen to migrate internally to the chain in select examples. Although the pivotal transformations failed, the deployment of a number of useful stereo-controlled reactions has ultimately resulted in the preparation of heavily substituted cis-decalins.     

Synthesis of (+)-didemniserinolipid B: application of a 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis

The synthesis of didemniserinolipid B utilizing a ketalization/ring-closing metathesis (K/RCM) strategy is described. In the course of this work, a novel 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis (RRCM) was developed, which increased the yield of the RCM. The resulting 6,8-dioxabicyclo[3.2.1]octene core was selectively functionalized by complimentary dihydroxylation and epoxidation routes to install the C10 axial alcohol. This bicyclic ketal core was further functionalized by etherification and an alkene cross metathesis with an unsaturated alpha-phenylselenyl ester en route to completing the total synthesis.     

Synthesis of a [2]catenane around a Ru(diimine)3(2+) scaffold by ring-closing metathesis of olefins

[reaction: see text] The synthesis of a ruthenium[2]catenane is described. One ring includes two 1,10-phenanthroline moieties, the other a bipyridinic unit. The interlocking ring system was formed by using a double ring closing metathesis reaction. Under irradiation, a rapid and selective decoordination of the bipyridinic fragment was observed, leading to a new catenane in which the metal is only coordinated to the bis-phenanthroline moiety.     

Relative rate profile for ring-closing metathesis of a series of 1-substituted 1,7-octadienes as promoted by a 4,5-dihydroimidazol-2-ylidene-coordinated ruthenium catalyst

[reaction: see text] This report details the kinetic responses of nine compounds of type 6 to ring-closing metathesis as promoted by 2 to give the identical product 7. The experimental observations have been subjected to Hammett analysis. The rho value for the composite aromatic derivatives (R = p-XC(6)H(4)-) differs from that of the aliphatic series, although both are negative because electron-donating groups accelerate the reaction.     

A formal total synthesis of eleutherobin using the ring-closing metathesis (RCM) reaction of a densely functionalized diene as the key step: investigation of the unusual kinetically controlled RCM stereochemistry

Asymmetric oxyallylation reactions and ring-closing metathesis have been used to synthesize compound 3, a key advanced intermediate used in the total synthesis of eleutherobin reported by Danishefsky and co-workers. The aldehyde 6, which is readily prepared from commercially available R-(-)-carvone in six steps in 30 % overall yield on multigram quantities, was converted into the diene 5 utilizing two stereoselective titanium-mediated Hafner-Duthaler oxyallylation reactions. The reactions gave the desired products (8 and 12) in high yields (73 and 83 %, respectively) as single diastereoisomers, with the allylic alcohol already protected as the p-methoxyphenyl (PMP) ether, which previous work has demonstrated actually aids ring-closing metathesis compared to other protective groups and the corresponding free alcohol. Cyclization under forcing conditions, using Grubbs' second-generation catalyst 13, gave the ten-membered carbocycle (E)-14 in 64 % yield. This result is in sharp contrast to similar, but less functionalized, dienes, which have all undergone cyclization to give the Z stereoisomers exclusively. A detailed investigation of this unusual cyclization stereochemistry by computational methods has shown that the E isomer of the ten-membered carbocycle is indeed less thermodynamically stable than the corresponding Z isomer. In fact, the selectivity is believed to be due to the dense functionality around the ruthenacyclobutane intermediate that favors the trans-ruthenacycle, which ultimately leads to the less stable E isomer of the ten-membered carbocycle under kinetic control. During the final synthetic manipulations the double bond of enedione (E)-16 isomerized to the more thermodynamically stable enedione (Z)-4, giving access to the advanced key-intermediate 3, which was spectroscopically and analytically identical to the data reported by Danishefsky and co-workers, and thereby completing the formal synthesis of eleutherobin.     

Combinatorial chemistry. Use of an intramolecular ruthenium catalyzed olefin/alkyne metathesis reaction in tandem with a Diels-Alder cycloaddition reaction to construct functionalized hexahydroisoindoles

We show here the first example of a ruthenium catalyzed ene-yne metathesis reaction in tandem with a Diels-Alder cycloaddition reaction to efficiently form highly substituted hexahydroisoindole ring systems on Wang resin. This approach was used to prepare a 4200 membered combinatorial library.     

Hetero-Diels-Alder reaction of propenenitriles with enol ethers: a convenient approach to functionalized 3,4-dihydro-2H-pyrans

The hetero-Diels-Alder reaction of 3-(N-acetyl-N-benzylamino)-2-formylprop-2-enenitrile with enol ethers yielded cis/trans diastereoisomers of 2-alkoxy-4-amino-3,4-dihydro-2H-pyran-5-carbonitriles in moderate yields. Acidic hydrolysis of cis-diastereoisomer in concentrated sulfuric acid gave 2-oxo-1,2-dihydropyrydine-3-carbaldehyde. The reaction of 2-benzoyl-3-heteroaromaticprop-2-enenitriles with enol ethers afforded diastereoisomeric cis/trans cycloadducts in good yields. The structure of the products is discussed in terms of configuration and preferred conformation.     

Derivatization of aromatic amines for analysis in ammunition wastewater II: Derivatization of methyl anilines by iodination with a Sandmeyer-like reaction

An analytical method for the determination of aromatic amines in water is introduced that uses iodination with a Sandmeyer-like reaction to replace the amino group by iodine in aqueous solution. The non-polar derivatives are extracted with pentane or toluene, separated with gas chromatography and sensitively detected with an ECD. Thirteen major metabolites of nitroaromatic explosives were investigated. The method was used to analyze these metabolites in water samples from the site of a former ammunition plant. The results are compared with the derivatization of aromatic amines via bromination of the aromatic ring. Received: 23 December 1996 / Revised: 31 January 1997 / Accepted: 8 February 1997     

A facile method for the preparation of hexafluoroisopropanol functionalized derivatives using hexafluoroacetone trihydrate via a carbonyl-ene reaction

Hexafluoroacetone trihydrate was shown to undergo an efficient carbonyl-ene reaction with a variety of alkenes in the presence of molecular sieves under microwave heating and conventional heating producing hexafluoroisopropanol functionalized derivatives in high yields.     

Unexpected dramatic substituent effect for tuning the selectivity in the double ring-closing metathesis reaction of N-containing tetraenes. An efficient synthesis of bicyclic izidine alkaloid skeletons

[reaction: see text] A double ring-closing metathesis reaction for the efficient construction of the fused bicyclic izidine alkaloid skeleton was developed. In this reaction, high selectivity was realized by tuning of electronic and steric effects of substituents in the N-containing tetraenes. It was observed that the reactivity of electron-rich carbon-carbon double bonds is higher than that of electron-deficient ones. A brief mechanistic study is also discussed.     

Derivatization of aromatic amines for analysis in ammunition wastewater II: Derivatization of methyl anilines by iodination with a Sandmeyer-like reaction

An analytical method for the determination of aromatic amines in water is introduced that uses iodination with a Sandmeyer-like reaction to replace the amino group by iodine in aqueous solution. The non-polar derivatives are extracted with pentane or toluene, separated with gas chromatography and sensitively detected with an ECD. Thirteen major metabolites of nitroaromatic explosives were investigated. The method was used to analyze these metabolites in water samples from the site of a former ammunition plant. The results are compared with the derivatization of aromatic amines via bromination of the aromatic ring.