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AlMe3 can promote the oxidative cyclization of eta2-alkene and eta2-ketone on nickel(0) to give an intriguing nickel-aluminum dinuclear complex having a bridging methyl group, which might be an intermediate for the nickel-catalyzed cycloisomerization of o-allylacetophenone or o-allylbenzophenone.
A concise total synthesis of 7-demethylpiericidin A1 has been completed. The synthesis features a titanium(II)-mediated cyclization of a (silyloxy)enyne as the key step and proceeds in nine steps from tiglic aldehyde.
Polystyrene macrocycles have been prepared from ATRP precursors by modification of the terminal bromide to an azide, followed by "click" cyclization with a pendant alkyne from the initiator. This route offers exceptional control over the size and polydispersity of the macrocyclic polymers, as well as providing tolerance to a number of functional groups.
A rhodium(I)-catalyzed tandem cyclization of alkynes has been developed. The reaction allows for multiple bond formations to occur at both the alpha- and beta-positions of alkynes under mild conditions to yield a variety of fused ring systems as the products. In the presence of triethylamine and the complex derived from [Rh(COD)Cl]2 and P(4-F-C6H4)3, a terminal alkyne is converted to a rhodium alkynyl species which reacts with a tethered alkyl halide at the beta-position to provide a beta,beta-disubstituted alkenylidene complex. The rhodium alkenylidene species then undergoes additional ring closures with a range of pendent functional groups such as alkene, hydroxyl, and phenyl groups through [2 + 2] cycloaddition, nucleophilic addition, and 6pi-electrocyclization processes, respectively.
The synthesis, properties and catalytic uses of phosphinoalkynes bearing bulky end caps at the alkyne termini, that is, tris[(triarylsilyl)ethynyl]phosphines are reported. The most salient feature of the new phosphines is the holey molecular shape possessing a deep and large-scale metal-binding cavity. The holey phosphines displayed remarkable rate enhancement in the gold(I)-catalyzed six- and seven-membered ring forming cyclizations of acetylenic keto esters and 1,7-enynes. It is proposed that the cavity in the ligand forces a nucleophilic center (enol or alkene) of the acetylenic compounds close to the gold-bound alkyne, making ring-closing anti attack feasible.
A novel class of tricyclic tropane analogues has been synthesized by making use of radical cyclization technology in combination with the Stille coupling reaction. As hybrids between tropanes and quinuclidines, these tropaquinuclidines represent a significant structural departure from many of the other classes of tropane ligands synthesized to date. This structure class is characterized by the boat conformation of the tropane ring and the orientation of the additional bridge (and therefore of the nitrogen lone pair) together with the unusual placement of the aromatic moiety. All compounds were tested for their ability to inhibit monoamine reuptake under identical conditions. The ability to inhibit reuptake of dopamine in comparison to cocaine is generally decreased in this series but for one compound. (1S,3R, 6S)-(Z)-9-(thienylmethylene)-7-azatricyclo[4.3.1.0(3, 7)]decane-2beta-carboxylic acid methyl ester (5h) exhibits reasonable activity at the dopamine transporter (DAT) (K(i) = 268 nM) and good activity at the norepinephrine transporter (NET) (K(i) = 26 nM). The potency and selectivity shown by some of these ligands for the NET, serotonine transporter (SERT), or NET/SERT is striking, particularly in view of the displacement of the aromatic ring in this series from its usual position at C-3 in the WIN analogues. Thus, (1S,3R,6S)-(Z)-9-(4-biphenylylmethylene)-7-azatricyclo[4.3.1 . 0(3,7)]decane-2beta-carboxylic acid methyl ester (5a) is a selective inhibitor of norepinephrine reuptake (K(i) = 12 nM). Its p-methoxy analogue 5c is a mixed inhibitor of norepinephrine and serotonin reuptake (K(i) = 187 nM at the NET and 56 nM at the SERT). The most active and selective compound we found in the present series is compound 8b [(1S,3R,6S)-2-(acetoxymethyl)-(Z)-9-(3, 4-dichlorophenylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decane ]. This compound is a potent (K(i) = 1.6 nM) and selective inhibitor of serotonin reuptake into rat midbrain synaptosomes. Its selectivity is about 400-fold over the NET and about 1000-fold over the DAT. The results of this study further demonstrate the possibility of tuning the selectivity of tropane analogues toward the SERT or NET binding site. The ligands disclosed herein provide additional pharmacological tools of use in attempting to correlate structure and transporter selectivity with in vivo studies of behavioral outcomes.
A synthetic procedure for the preparation of imidazolidinediones by the base-catalyzed cyclization of propargylureas is described. This method appears to be the most versatile way of obtaining these compounds containing tertiary groups substituted on ring-nitrogen number 3. One of these derivatives, 3-tert-butyl-5,5-dimethyl-2,4-imidazolidinedione (1a), has shown a moderate level of subcutaneous metrazole seizure threshold activity (scMet indicates potential for control of petit mal epileptic seizures) in control screens on mice, as determined by the National Institute of Neurological and Communicative Disorders and Stroke.
A new synthesis of Mannich bases of rifamycin SV using the Borch2 procedure with rifaldehyde is described. This new synthesis offers two advantages over the previously published method. It provides a route to monoalkyl-aminomethylrifamycins (le-h) and to unsubstituted aminomethylrifamycins that were not accessible by the old procedure. The new method also offers a preparative route to Mannich bases 1a and 1b were needed in multigram quantities for biological testing. In addition, the cyclization of certain of the monoalkylaminomethylrifamycins to the novel N,15-didehydro-15-epi[methano(alkylimino)]rifamycin SV derivatives (2) is described. The anticellular and antiviral effects of representatives of both series of compounds against cultured mouse cells and murine oncornavirus are are discussed.
s-Triazolo[4,3-a][1,4]benzodiazepines bearing various substituents in the 1 position were prepared by oxidative cyclization of the appropriate aldehyde hydrazones of 2-hydrazinobenzodiazepines. Diethyl azodicarboxylate and activated manganese dioxide were used as oxidizing agents. The new triazolo compounds were active in the CNS tests but none of them reached the potency of the known triazolobenzodiazepines.
Triene 5 has been prepared by the E-selective olefination of aldehyde 12 with the ylide 11. Several alternative syntheses of 12 were evaluated, and the successful route involved conversion of 22 into the vinyl ether 23 by Petasis olefination, followed by Claisen rearrangement. Diels-Alder cycloaddition of 5 with 4 gave the adduct 6 in 77% yield, and Reformatsky cyclization under dilution conditions afforded 10 (67%). After conversion to enol silane 32, oxidation with dimethyldioxirane produced 34. Conversion to a key intermediate 38 using electrophilic selenenylation and selenoxide rearrangement, followed by enolate alkylation and deprotection, gave 43. The X-ray crystal structure of 43 was determined to prove the stereochemistry.
Studies are reported on the use of either a 7-exo radical cyclization or an intramolecular Heck reaction as the key step for the construction of the benzophenone fragment of the PKC inhibitor, balanol. Whereas, the former approach was unsuccessful, the Heck reaction proved to be viable for the coupling of two fully functionalized aryl subunits affording regioselectively a biaryl seven-membered lactone with an exocyclic alkene as the major component, in contrast to the competing eight-membered ring lactone. Hydrolysis of the lactone followed by oxidative cleavage of the alkene with ruthenium tetraoxide completed this short synthesis of the benzophenone unit.
The first total synthesis of the oxindole alkaloid gelsedine (1) starting from (S)-malic acid is described. The key step is a novel iodide-promoted intramolecular reaction of an allene with an N-acyliminium ion intermediate which provided in a single step the bicyclic vinyl iodide 11. Other important steps are the highly stereoselective Pd-catalyzed Heck cyclization of N-methylanilide 23a which led to the desired spiro-oxindole 24a, the fully regioselective intramolecular oxymercuration of 25a to the desired cyclic ether, and the remarkable oxindole N-demethylation of 29 via a radical mechanism by using dibenzoyl peroxide. The total synthesis was concluded by the stereoselective introduction of the ethyl group from the bis-Boc compound 41 followed by methoxylation of the oxindole nitrogen. This total synthesis leads to the unnatural (+)-enantiomer of gelsedine in 21 steps and 0.10% overall yield.
1,5,6,10b-Tetrahydropyrrolo[2,1-alpha]isoquinolin-3(2H)-ones 17a,b, 17d,e, and 5,12b-dihydroisoindolo[1,2-alpha]isoquinolin-8(6H)-ones 22a-e were prepared by intramolecular cyclizations of 1-(2-arylethyl)-5-benzotriazolyl-pyrrolidin-2-ones 15a,b, 15d,e, and 3-benzotriazolyl-2-(2-arylethyl)-1-isoindolinones 20a-e, respectively, in the presence of titanium chloride. Products from chiral amines were obtained with stereoselectivities of > or = 94%.
Syntheses of the first bridgehead sultams and the only known bridgehead disulfonimide are described. Both approaches capitalize on the electrophilicity of alpha-sulfonyl radicals and their propensity to undergo intramolecular ring closure. Where double bonds are concerned, 5-exo and 6-exo pathways operate preferentially as long as structural strain is not excessive. When the reaction center is a carbon-carbon triple bond, the first cyclization gives rise to vinyl radicals that hold sufficient reactivity to capture solvent benzene. In the case of 45, this sequential reaction leads importantly to the introduction of a styrene functionality sufficiently activated to allow a second ring closure to be kinetically feasible. The solid-state structural features of 12 and 17 have been elucidated by X-ray crystallographic methods. Despite key differences from the norm in the alignment of the nitrogen lone pair relative to the adjacent sulfonyl groups, these compounds exhibit good hydrolytic stability. For 13, generation of the alpha-sulfonamide carbanion is possible and regiospecific oxidation with chromyl acetate has been achieved.
We report a new route to F(2t)-IsoP (formerly named 8-epi-PGF(2alpha)) using a biomimetic radical cyclization of a highly functionalized C20 precursor. The strategy employed gives a beta-hydroxy free radical followed by molecular oxygen trapping, which is an unusual method for quenching carbon free radicals. We observed the formation of unique diastereoisomers (15R)- and (15S)-F(2t)-IsoP. This result is consistent with a strong stereoelectronic control associated with a steric effect initiated by the side chains alpha and omega on the cyclopentane ring.
A convergent synthetic route to the (E)FGH ring system 4 of ciguatoxins, the causative toxins for ciguatera fish poisoning, has been developed. The synthesis features convergent coupling to form dioxane acetal, regioselective acetal cleavage by diethylaluminum phenylthiolate or diisobutylaluminum phenylselenolate followed by intramolecular radical cyclization to construct the oxepane ring G, and a ring-closing metathesis reaction to form the hexahydrooxonine ring F. The hexahydrooxonine ring F of tetracyclic model system 4 existed as a 5:1 equilibrium mixture of two conformers (UP and DOWN conformers), with the UP one predominating. This is the first illustration that reproduces the preference for the UP conformer over the DOWN one, which preference was observed for natural ciguatoxins.
Bicyclization of peptide acetals via nucleophilic attack of a phenyl group on an endocyclic acyliminium ion 4 was explored as a route to novel amino acid derived heterocycles and peptidomimetic scaffolds. In the presence of protic acid, bridged structures such as 6 are formed readily from phenylalanine derivatives, but the fused-ring analogues 5 could not be obtained in good yield. In contrast, radical cyclization of the bromophenyl dihydropyrazinone 7 provides an effective alternative for the synthesis of 5 (n = 0, 1, 2). Additional versatility in this process was demonstrated by efficient synthesis of a different fused ring system, represented by the antihelmintic praziquantel, 8.
(-)-Neplanocin A (1), S-adenosylhomocystein hydrolase inhibitor, was synthesized. The characteristic of this synthesis is a stereoselective construction of five-membered ring of neplanocin A by intramolecular aldol reaction of the lithium enolate that was generated by conjugate addition of lithium thiolate. TBS-protected chiral omega-oxo-alpha,beta-unsaturated ester 16, which was prepared from D-mannitol, was treated with 1.2 equiv of lithium benzylthiolate in THF at -20 degrees C to give three separable cyclization products in good yields and stereoselectivity. After conversions of protective groups, the benzylsulfanyl part of 21 was removed by oxidation to sulfoxide and subsequent thermal elimination to give the requisite double bond. Through the functional group transformations of 30, total synthesis of (-)-neplanocin A (1) was accomplished.