Thermodynamic and kinetic factors in the aza-Cope rearrangement of a series of iminium cations

The effects of C-C bond conformation, double bond geometry, and relative stereochemistry on the kinetic and thermodynamic stability of 30 iminium cations as they undergo an aza-Cope rearrangement have been examined via density functional calculations for the purposes of predicting stereoselectivity in the reaction sequence. DFT predicted transition states were consistent with experimentally observed stereoselectivities. The calculations were then extended to the rearrangements of other iminium cations with varying substitution patterns to identify trends in rearrangement pathways. These trends should provide insight into controlling stereoselectivity in this reaction sequence.     

Aza-cope rearrangement-mannich cyclizations for the formation of complex tricyclic amines: stereocontrolled total synthesis of (+/-)-gelsemine

A detailed examination of the use of aza-Cope rearrangement-Mannich cyclization sequences for assembling the azatricyclo[4.4.0.0(2,8)]decane core of gelsemine is described. Iminium ions and N-acyloxyiminium ions derived from endo-oriented 1-methoxy- or 1-hydroxybicyclo[2.2.2]oct-5-enylamines do not undergo the first step of this sequence, cationic aza-Cope rearrangement, to form cis-hydroisoquinolinium ions. However, the analogous base-promoted oxy-aza-Cope rearrangement does take place to form cis-hydroisoquinolones containing functionality that allows iminium ions or N-acyloxyiminium ions to be generated regioselectively in a subsequent step. Mannich cyclization of cis-hydroisoquinolones prepared in this way efficiently assembles the azatricyclo[4.4.0.0(2,8)]decane unit of gelsemine. Using a sequential base-promoted oxy-aza-Cope rearrangement/Mannich cyclization sequence, gram quantities of azatricyclo[4.4.0.0(2,8)]decanone 18, a central intermediate in our total of (+/-)-gelsemine, were prepared from 3-methylanisole in 12 steps and 16% overall yield.     

A formal total synthesis of (-)-FR901483, using a tandem cationic aza-Cope rearrangement/Mannich cyclization approach

A formal total synthesis of the immunosuppressant FR901483 has been accomplished. The key step in the synthesis utilizes a tandem cationic aza-Cope rearrangement/Mannich cyclization reaction for accessing the unprecedented bridging tricyclic azaspirane substructure of this compound. The tandem reaction proceeds through a bridgehead iminium ion, a functionality that has rarely been explored in the context of natural product syntheses. Improved stereoselectivity was observed in an aldol reaction when using a Boc-protected amino aldehyde and zinc chloride as an additive. A stereoselective epimerization of the aldehyde-containing stereocenter was achieved with l-phenylalanine upon completion of the Mannich cyclization. Finally, this synthesis is the only one to date that controls the stereochemistry of the oxygen-bearing stereocenters. All other synthetic routes required late stage adjustments to at least one of these stereocenters.     

Tandem cationic aza-cope rearrangement-Mannich cyclization approach to the core structure of FR901483 via a Bridgehead iminium ion

[reaction in text] An approach to the potent immunosuppressant FR901483 is described. This route utilizes a tandem cationic aza-Cope rearrangement-Mannich cyclization to generate the core structure of this compound. In addition, this is the first demonstration of this tandem reaction passing through a bridgehead iminium ion.     

Stereochemistry as a tool in deciphering the processes of a tandem iminium cyclization and Smiles rearrangement

To understand the detailed mechanism of a recently reported tandem iminium cyclization and Smiles rearrangement, the reaction processes of a chiral substrate were investigated by monitoring its stereochemical courses. Under the tandem reaction conditions, chiral aldehyde 1 derived from l-prolinol led to two surprising results. First, the iminium cyclization gave a diastereomeric mixture with the cis-configured product as the predominant one. Second, Smiles rearrangement of both cis- and trans-2 led to the same product 3a directly derived from the trans isomer. The former was rationalized by the postulation of a Cram's chelate transition state leading to the cis product as kinetically favored. The latter was due to the equilibration between the trans/cis pair involving a carbocation intermediate and the steric hindrance, which prevented the cis isomer from undergoing the intramolecular nucleophilic substitution. This hypothesis was further supported by the results of a competition experiment in which the addition of 1 equiv of p-methoxyaniline in the rearrangement step led to a significant amount of anilinyl-exchanged rearrangement product.     

Azidomercurations of alkenes: mercury-promoted Schmidt reactions

Azides bearing a suitably disposed alkene, when treated with either mercuric perchlorate or mercuric trifluoromethanesulfonate, produce bicyclic iminium ions. This new version of the Schmidt reaction proceeds by capture of the mercuronium ion intermediate by the azide to produce an aminodiazonium ion, which suffers a 1,2-shift to give an iminium ion (e.g., 10 --> 16 --> 17 --> 18). Reduction of the iminium ion may then be carried out to produce an amine. Compared to earlier work on the protic acid-promoted intramolecular Schmidt reaction of azido-alkenes, the mercury-promoted Schmidt reaction has several advantages. First, the acid-promoted Schmidt reaction of azido-alkenes requires that the intermediate carbocations be tertiary, allylic, benzylic, or propargylic. The mercury-promoted method has no such limitation; thus even 1,2-disubstituted alkenes may be used. Second, the mercury-promoted method is milder, allowing the presence of acid-sensitive functionality. The protic version, typically employing trifluoromethanesulfonic acid, is limited in its functional group tolerance. Third, whereas carbocation rearrangement is often observed prior to cyclization/rearrangement in the acid-promoted Schmidt reaction, the mercury-promoted method avoids this problem. Fourth, the presence of the mercurio group during the rearrangment may alter the regioselectivity of the 1,2-migration. Finally, the mercury-bearing iminium ions that are the result of the Schmidt reaction were found to be sensitive to protodemercuration, precluding their use in other transformations.     

Total Synthesis of (±)-Gelsemine

A complex molecular reorganization ( 1 → 2 ), a sequential anionic aza-Cope rearrangement and Mannich cyclization, and an unprecedented intramolecular Heck reaction of the tetrasubstituted double bond of a vinylogous carbamate are key steps in a new total synthesis of (±)-gelsemine ( 3 ). MOM=methoxymethyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.     

Tropylium ion mediated α-cyanation of amines

Tropylium ion mediated α-cyanation of amines is described. Even in the presence of KCN, tropylium ion is capable of oxidizing various amine substrates, and the resulting iminium ions undergo salt metathesis with cyanide ion to produce aminonitriles. The byproducts of this transformation are simply cycloheptatriene, a volatile hydrocarbon, and water-soluble potassium tetrafluoroborate. Thirteen total substrates are shown for the α-cyanation procedure, including a gram scale synthesis of 17β-cyanosparteine. In addition, a tropylium ion mediated oxidative aza-Cope rearrangement is demonstrated.     

Several convenient methods for the synthesis of 2-amido substituted furans

Several new methods for the synthesis of differently substituted 2-amidofurans are described. The thermolysis of furan-2-carbonyl azide results in a Curtius rearrangement and the resulting furanyl isocyanate was trapped with various organometallic reagents. A second method consists of a C-N cross-coupling reaction of a bromo-substituted furan with various amides, carbamates, and lactams. The CuI-catalyzed cross-coupling reaction between furanyl bromides and amides furnished 2- and 3-substituted amidofurans in 45-95% yield. The third protocol used involves the reaction of cyclic carbinol amides with triflic anhydride. The reaction proceeds under very mild conditions to provide alpha-(trifluoromethyl)sulfonamido-substituted furans in high yield. The resulting iminium ion derived from the reaction of the hydroxy pyrrolidinone with Tf(2)O undergoes a facile ring opening as a consequence of the adjacent hydroxyl group to produce an imino triflate intermediate. Subsequent cyclization of this highly electrophilic imine with the oxygen atom of the adjacent carbonyl group leads to an imino dihydrofuran that reacts further with another equivalent of Tf(2)O to give the observed product.     

Synthesis of non-natural l-alanine derivatives using the aza-Cope–Mannich reaction

Non-natural l-alanine derived trans-octahydrocyclohepta[b]pyrroles were synthesized with high enantiomeric purity using the aza-Cope–Mannich reaction. The study showed that the conditions of the aza-Cope–Mannich reaction and metal catalysed cyclization are mild enough to be applied to the synthesis of molecules with stereocenters, which are prone to racemization. We believe that these compounds will be of interest to medicinal chemists.     

Total synthesis of (±)-cortistatin J from furan

A concise, diastereoselective total synthesis of (±)-cortistatin J has been completed in 20 steps from furan. Key steps include an intramolecular [4 + 3] cyclization of a disubstituted furan with a (Z)-2-(trialkylsilyloxy)-2-enal to construct the tetracyclic core and a (Z)-vinylsilane/iminium ion cyclization to form the A ring.     

Iron(III)-catalyzed consecutive aza-Cope-Mannich cyclization: synthesis of trans-3,5-dialkyl pyrrolidines and 3,5-dialkyl-2,5-dihydro-1H-pyrroles

An efficient alkene aza-Cope-Mannich cyclization between 2-hydroxy homoallyl tosylamine and aldehydes in the presence of iron(III) salts to obtain 3-alkyl-1-tosyl pyrrolidines in good yields is described. The process is based on the consecutive generation of a γ-unsaturated iminium ion, 2-azonia-[3,3]-sigmatropic rearrangement, and further intramolecular Mannich reaction. Iron(III) salts are also shown to be excellent catalysts for the new aza-Cope-Mannich cyclization using 2-hydroxy homopropargyl tosylamine.     

Synthesis of substituted tetrahydropyridines by cyclizations of silicon-containing iminium ions

Trans-2,6-disubstituted-1,2,5,6-tetrahydropyridines are formed stereoselectively from the cyclization of silicon-containing iminium cations 5 if the nitrogen substituent R¹ is an alkyl group. In contrast, cyclization of the corresponding NH or N-acyl iminium ions occurs in a stereorandom fashion. Nonracemic tetrahydropyridines cannot be prepared in this way, since both iminium ion and N-acyliminium ion intermediates racemize prior to cyclization.     

1,2-silyl-migrative cyclization of vinylsilanes bearing a hydroxy group: stereoselective synthesis of multisubstituted tetrahydropyrans and tetrahydrofurans(1)

Acid-catalyzed intramolecular addition of a hydroxy group to alpha-alkylated vinylsilanes has been studied. Treatment of (Z)-5-alkyl-5-silyl-4-penten-1-ols 1 (R = alkyl) with 5 mol % TiCl(4) in CHCl(3) gave trans-2-alkyl-3-silyltetrahydropyrans 2 exclusively (trans/cis = >99/1 to 97/3). The cyclization efficiency and rate strongly depended on the geometry of the C-C double bond and the silyl group. The use of (E)-vinylsilanes resulted in lower yields with poor cis-selectivity. In the cyclization of (Z)-1 (R = Bu), the silyl group used, the reaction time, and the yield of 2 were as follows: SiMe(2)Ph, 9.5 h, 75%; SiMe(3), 7.5 h, 66%; SiMePh(2), 24 h, 58%; SiMe(2)-t-Bu, 0.75 h, 85%; SiMe(2)Bn, 1.5 h, 78%. This 1,2-silyl-migrative cyclization could be applied to stereoselective synthesis of trisubstituted tetrahydropyrans. The acid-catalyzed reaction of 1-, 2-, or 3-substituted (Z)-5-silyl-4-nonen-1-ols 8 gave r-2,t-3,c-6-, r-2,t-3,t-5-, or r-2,t-3,c-4-trisubstituted tetrahydropyrans with high diastereoselectivity, respectively. (Z)-4-Alkyl-4-silyl-3-buten-1-ols 5 as well as 1 underwent the 1,2-silyl-migrative cyclization to give 2-alkyl-3-silyltetrahydrofurans 6 with high trans-selectivity. This silicon-directed cyclization was also available for the stereoselective synthesis of tri- and tetrasubstituted tetrahydrofurans.     

Synthesis of conformationally constrained 5,6,7, 8-Tetrahydroimidazo[1,5-a]pyridine inhibitors of farnesyltransferase

[reaction: see text] Synthesis of the 8-amino-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ring system was accomplished by intramolecular cyclization of an iminium ion, derived from condensation of an amine and a substituted gamma-(1-imidazolyl)butyraldehyde. The reaction was used to produce conformationally restricted farnesyltransferase inhibitor analogues which exhibit improved in vivo metabolic stability.     

Triflic anhydride mediated cyclization of 5-hydroxy-substituted pyrrolidinones for the preparation of alpha-trifluoromethylsulfonamido furans

The reaction of alpha-angelica lactone with alkylamines under aqueous conditions afforded 5-hydroxy-5-methylpyrrolidinones in high yield. When the reaction was carried out under anhydrous conditions, the only products obtained were the corresponding 4-oxopentanoic acid amides. Treatment of either class of compound with triflic anhydride (Tf(2)O) in pyridine resulted in the formation of various substituted sulfonamidofurans. The suggested mechanism involves initial formation of an iminium ion which is subsequently transformed into a transient imino triflate. Cyclization of the highly electrophilic imine onto the oxygen atom of the adjacent carbonyl group generates an imino dihydrofuran intermediate. This species reacts further with another equivalent of Tf(2)O to give the observed product. The nature of the Lewis acid used was found to affect the outcome of the cyclization reaction. In certain cases, the sulfonamide furan was utilized as a cycloaddition substrate for the synthesis of indolines and related heterocyclic systems.     

Pyrrolo-dihydropteridines via a cascade reaction consisting of iminium cyclization and O-N Smiles rearrangement

The reactions of 5-pyrrolyl-pyrimidinyloxyacetaldehyde or methyl ketone with primary amines yielded hydroxymethylpyrrolopteridine derivatives via a cascade of iminium cyclization and O-N Smiles rearrangement. The present cascade exhibited a different profile compared to the previously reported ones, which consisted of N-N Smiles rearrangement. Lewis acid (TiCl₄) under carefully controlled conditions was employed to suppress the competing formation of imine dimers to give the desired heterocycles. A plausible mechanism involving the iminium cyclization and Smiles rearrangement is proposed. This methodology has been used to generate a series of 6-hydroxymethylpyrrolo[1,2-f]pteridine derivatives with potential biological activities.     

Organocatalytic Enantioselective Vinylcyclopropane-Cyclopentene (VCP-CP) Rearrangement

We have demonstrated that the catalytic and enantioselective vinylcyclopropane-cyclopentene rearrangement can be carried out on (vinylcyclopropyl)acetaldehydes through activation via enamine intermediates. The reaction makes use of racemic starting materials that, upon ring opening facilitated by the catalytic generation of a donor-acceptor cyclopropane, deliver an acyclic iminium ion/dienolate intermediate in which all stereochemical information has been deleted. The final cyclization step forms the rearrangement product, showing that chirality transfer from the catalyst to the final compound is highly effective and leads to the stereocontrolled formation of a variety of structurally different cyclopentenes.     

Lewis acid catalyzed stereoselective carbosilylation. Intramolecular trans-vinylsilylation and trans-arylsilylation of unactivated alkynes.

Intramolecular trans-vinylsilylation using silicon-tethered alkynylvinylsilanes 3b-c was catalyzed dramatically by Lewis acids such as EtAlCl(2) to give the corresponding six-membered silacycles 4b-c in high yields. The reaction proceeded via an exo-mode cyclization. In addition to the vinylsilylation, the intramolecular trans-arylsilylations using carbon-tethered alkynylarylsilanes 8a-b were also catalyzed by Lewis acids such as HfCl(4) to give six- and seven-membered cyclic (E)-vinylsilanes 9a-b, respectively. The cyclization of silicon-tethered substrates 13a-d afforded five- and six-membered silacycle products 14a-d in low to high yields. All arylsilylation reactions proceeded via an exo-mode fashion exclusively.     

Hydrolysis of alpha- and beta-glycosides. New experimental data and modeling of reaction pathways

[reaction: see text] The cyclization of oxocarbenium ion conformers 6alpha and 6beta (from 11E and 11Z) gave only the beta-glycoside 1beta, and the addition of methanol to the oxocarbenium ion 3 yielded mainly the alpha-glycoside 1alpha with both experiments being carried out under kinetically controlled conditions. RHF/6.31G calculations reproduce well these experimental results and show that the endocyclic and the exocyclic C-O bond cleavage processes can compete in the hydrolysis of 1beta, whereas 1alpha gets hydrolyzed by exocyclic C-O bond cleavage only.