[2+2] Photocycloaddition of 3‐Alkenyloxy‐2‐cycloalkenones: Enantioselective Lewis Acid Catalysis and Ring Expansion

By application of substoichiometric amounts (50 mol %) of a chiral Lewis acid, the intramolecular [2+2] photocycloaddition of the title compounds was achieved with high enantioselectivity (up to 94 % ee). Upon cleavage of the cyclobutane ring the resulting tricyclic products underwent ring‐expansion reactions under acidic conditions and formed anellated seven‐ or eight‐membered‐ring systems without racemization. The ring expansion could be combined with a diastereoselective reduction (triethylsilane) or allylation (allyltrimethylsilane) upon BF₃ catalysis (48–87 % yield).     

Lewis acid-catalyzed stereospecific ring expansion of aziridine-2-carboxylates to imidazolidin-2-ones

Lewis acid-catalyzed ring expansion reaction of chiral aziridine-2-carboxylate proceeds regio- and stereospecifically to yield enantiomerically pure 4-functionalized imidazolidin-2-ones in high yields.     

Synthesis of enantiopure dihydropyranones: aldol-based ring expansion of dihydrofurans

[reaction: see text] The stereoselective Birch reduction of 3-methyl-2-furoic acids using a readily available chiral auxilairy is described; by coupling this process to an oxidative cleavage/aldol ring closure sequence we were able to produce highly functionalized and enantiopure dihydropyranones in high yield. This sequence has ample flexibility built into it, either by the use of different electrophiles during reductive alkylation or by subsequent derivatization of the dihydropyranone after ring expansion.     

Efficient route to 2H-1,3-oxazines through ring expansion of isoxazoles by rhodium carbenoids

Studies related to the total synthesis of elisabethin C led to the discovery of a rhodium-catalyzed cascade sequence involving isoxazole ring expansion and a [4+3] cycloaddition. The scope of the isoxazole ring expansion was explored, resulting in the synthesis of a range of 2H-1,3-oxazines in 47-96% yield.     

I2-Catalyzed enantioselective ring expansion of beta-lactams to gamma-lactams through a novel C3-C4 bond cleavage. Direct entry to protected 3,4-dihydroxypyrrolidin-2-one derivatives

Molecular iodine (10 mol%) efficiently catalyzes the ring expansion of 4-oxoazetidine-2-carbaldehydes in the presence of tert-butyldimethyl cyanide to afford protected 5-cyano-3,4-dihydroxypyrrolidin-2-ones with good yield and high diastereoselectivity, through a novel C3-C4 bond cleavage of the beta-lactam nucleus.     

Use of temporary tethers in the intramolecular [2+2] photocycloaddition reactions of tetrahydrophthalimide derivatives: a new approach to complex tricyclic lactones

The intramolecular [2+2] photocycloaddition reactions of a series of alkenols tethered to ethanolamine, l-(+)-valinol and R-(−)-2-phenylglycinol derived 3,4,5,6-tetrahydrophthalimides via a carbonate or silicon linkage have been examined. These [2+2] photocycloadditions gave the corresponding cyclobutanes in high yield with complete endo control in all cases and with diastereoselectivities as high as 8:1 with the chiral tethers. The cleavage of the temporary tethers by either desilylation or hydrolysis provided the endo diols. Cleavage of the ethanolamine linkage by reduction/hydrolysis precipitated an acid-catalysed fragmentation/ring expansion sequence to generate complex tricyclic lactones.     

Efficient Synthesis of (±)‐Horsfiline through the MgI2‐Catalyzed Ring‐Expansion Reaction of a Spiro[cyclopropane‐1,3′‐indol]‐2′‐one

We report a short synthetic route to (±)‐horsfiline that provides the racemate in five steps from commercially available, substituted isatin in 41% overall yield. Efficient entry into the spiro[oxindole‐pyrrolidine] ring system is possible through the application of the cyclopropane opening/ring expansion chemistry we have described with MgI₂ as a bifunctional catalyst.     

Unexpected Ring Expansion of the (3aS,6aR)‐γ‐Thiolactone Moiety during the Introduction of the (+)‐Biotin Side Chain

The reaction of vinylmagnesium bromide with the (3aS,6aR)‐γ‐thiolactone 2 in THF afforded, after unexpected ring expansion of the γ‐thiolactone moiety, the seven‐membered‐ring ketone 5 in excellent yield, instead of the expected tertiary alcohol 3 .     

A versatile new strategy for the synthesis of tropolones

Swern-type oxidation of various 7-halogenobicyclo[4.1.0]heptane-2,3- or -3,4-diols affords the corresponding bicyclic diketones which undergo ^{in situ} ring expansion and loss of hydrogen halide to give α-tropolones in high yield. The quantitative conversion of the isolable 1,4-diketone 26 into the γ-tropolone acetate 27 has been achieved.     

Stimuli‐Responsive Frustrated Lewis‐Pair‐Type Reactivity of a Tungsten Iminoazaphosphiridine Complex

Reactions of 3‐imino‐azaphosphiridine complexes 1 a,b with carbodiimides 2 a,b , isocyanates 3 a,b , and carbon dioxide are described. Whereas exchange of the carbodiimide unit occurs in the first case, an overall ring expansion takes place with phenyl isocyanate ( 3 a ) and carbon dioxide to yield complexes 4 and 5 bearing novel 1,3,5‐oxazaphospholane ligands; the isopropyl derivative 3 b did not react under these conditions. DFT calculations provide insight into the pathway of the reaction with carbon dioxide with model complex 1 c , revealing effects of initial non‐covalent interactions with the substrate onto the ring bonding, thus triggering an initially masked frustrated Lewis‐pair‐type behavior.     

Nickel-catalyzed

Oxabenzonorbornadienes 1 and 2 and azabenzonorbornadiene 3 undergo [2+2] cycloaddition with alkynes (PhC triple bond Ph, PhC triple bond CMe, PhC triple bond CCO2Et, PhC triple bond CCH(OEt)2, and HC triple bond C(CH2)4Me) in the presence of [Ni(PPh3)2Cl2], PPh3, and Zn powder in toluene to afford the corresponding exo-cyclobutene derivatives 4a-e, 5a-e, and 6 in fair to excellent yields. Under similar conditions. EtCO2C triple bond CCO2Et does not react with 1 in toluene to give the [2+2] cycloaddition product, but in acetonitrile, the catalytic [2+2] cycloaddition proceeds and cycloadduct 4 f is isolated in 83% yield. At high temperature, these cyclobutene derivatives readily undergo ring expansion to yield the corresponding 8-membered carbocyclic dienes. Thus, flash vacuum pyrolysis of 4a, 4d, 4f, 6, and 14 at 500 degrees C affords dienes 13a-d and 15 in 70-96% yields. This interesting ring expansion may be viewed as the insertion of an alkyne moiety into the carbon-carbon double bond of a cyclic olefin resulting in the enlargement of the ring by two carbons. Compound 13a is readily deoxygenated by TiCl4 and Zn in THF to give a cyclooctatetraene derivative 16 in 89% yield.     

A highly efficient method for one-carbon ring expansion. Preparation of 1-alkoxy-2-methylenecycloalkanes

ZnBr₂ induces a facile one-carbon ring expansion of 1-(TMS-methyl)-cycloalkanecarbacetals to yield the corresponding 1-alkoxy-2-methylenecycloalkanes, whereas a similar transformation can be performed efficiently from the parent aldehydes under the influence of TMS-OTf (1 mol%) and TMS-OMe (2 equiv).     

Preparation and polymerization of the two isomeric (chloromethyl)oxetanes

2-(Chloromethyl)oxetane was prepared in 8% overall yield from 2-propen-1-ol by protection of the alcohol with dihydropyran, epoxidation, ring expansion with dimethylsulfoxonium methylide, acid deprotection, and chlorination with triphenylphosphine in CCl₄. 3-(Chloromethyl)oxetane was prepared in 22% overall yield by hydroboration-oxidation of 3-chloro-2-chloromethyl-1-propene followed by base-catalyzed cyclization. Each of the oxetanes was converted to the corresponding elastomeric homopolymer by treatment with a triethylaluminum–acetylacetone–water mixture. Poly[2-(chloromethyl)oxetane] was found to be similar to polyepichlorophydrin in reactivity toward benzoate ion, whereas poly[3-(chloromethyl)oxetane] is more reactive by a factor of 2.     

Enantiocontrolled Total Synthesis of (−)‐Mersicarpine

A racemic synthesis of mersicarpine ( 1 ) was achieved by the Mizoroki–Heck reaction and a DIBALH‐mediated reductive ring‐expansion reaction. Based on a first‐generation synthesis, a second‐generation enantiocontrolled total synthesis of (?)‐mersicarpine ( 1 ) was achieved by an 8‐pot/11‐step sequence in 21 % overall yield from commercially available 2‐ethylcyclohexanone. Subjection of a ketoester, which was prepared by an asymmetric Michael addition (according to the protocol by d’Angelo and Desmaële), and phenylhydrazine to modified Fischer indole conditions provided a six‐membered tricyclic indole. Benzylic oxidation and subsequent oxime formation provided a ketoxime, which was treated with diisobutylaluminum hydride (DIBALH) to construct the characteristic azepinoindole skeleton in good yield. In the DIBALH‐mediated reductive ring‐expansion reaction, gradually increasing the reaction temperature and in situ‐protection of the nitrogen in an oxygen‐sensitive azepinoindole with a benzyloxycarbonyl (Cbz) group were crucial for the high‐yielding process. With these methodologies, the short‐step and efficient synthesis of (?)‐mersicarpine was accomplished. Several synthetic efforts are also described.     

Synthetic studies on cyathins: enantioselective total synthesis of (+)-allocyathin B2

[reaction: see text] The enantioselective total synthesis of (+)-allocyathin B(2) has been achieved. Our approach features a convergent enantioselective construction of the 5-6-7 tricyclic core system using the originally developed chiral building blocks via asymmetric catalysis, the intramolecular aldol reaction in high yield, successful samarium diiodide-mediated ring expansion, and a newly developed double-bond installation method.     

Remarkable synthesis and structure of allene type zerumbone

The ring expansion of zerumbone to a 12-membered ring was studied via a ring opening system or a ring closure system of zerumbone. We succeeded in the synthesis of a zerumbone derivative with 12-membered ring, an allene type zerumbone. For the first time, a Doering-LaFlamme allene synthesis method was adopted and the structure was confirmed by monocrystal X-ray diffraction. It was obtained in total 27.7% yield from zerumbone. We believe that this compound is not only an important building block in synthesizing the BC ring of paclitaxel, but also plays an important role in a novel structure formation and a reactive discovery.     

Study of the oxidative half‐reaction catalyzed by a non‐heme ferrous catalytic center by means of structural and computational methodologies

Deacetoxycephalosporin C synthase (DAOCS) is a mononuclear ferrous enzyme that catalyzes the expansion of the five‐membered thiazolidine ring of the penicillin nucleus into the six‐membered dihydrothiazine ring of the cephalosporins. In the first half‐reaction with dioxygen and 2‐oxoglutarate, a reactive iron–oxygen species is produced that can subsequently react with the penicillin substrate to yield the cephalosporin. We describe quantum mechanical calculations of the first part of the reaction based on the high‐resolution structures of the active site of DAOCS and its complexes with ligands. These studies are aimed at understanding how the reactive species can be produced and contained in the active site of the enzyme. The results demonstrate the priming of the active site by the co‐substrate for oxygen binding and hint to the presence of a stable iron–peroxo intermediate in equilibrium with a more reactive ferryl species and the formation of CO₂ as a leaving group by decarboxylation of 2‐oxoglutarate. A conclusion from these studies is that substitution of CO₂ by the penicillin substrate triggers the oxidation reaction in a booby‐trap‐like mechanism. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Synthesis of eleven-membered carbocycles via a homo-Cope type of five-carbon ring expansion reaction utilized β-(hydroxymethyl)allylsilane

Eleven-membered carbocycles were synthesized from six-membered compounds fitted with a β-(hydroxymethyl)allylsilane unit via the title reaction. Namely, trans- and cis-(E)-2-(trimethylsilylmethyl)-3-(2-vinylcyclohex-1-yl)prop-2-en-1-ol were treated with Tf₂O in CH₂Cl₂ in the presence of 2,6-lutidine to afford (1E)-3-methylenecycloundeca-1,6-diene in good yield. The geometry of the product was shown to depend upon the trans- and cis-substitution pattern on the cyclohexane ring of the substrates; i.e. trans-isomer afforded (6E)-product exclusively and cis-isomer afforded the mixture of (6E)- and (6Z)-product in 1:2 ratio. The (Z)-substrate with respect to allylsilane moiety afforded the same ring expansion product, however, the yield was lower than the reaction with the (E)-substrate. The substrates bearing t-butyl or benzyloxy substituents on the cyclohexane ring also afforded the product analogously, indicating that the reaction depends upon the conformation of the substrate. On the other hand, the substrate bearing isopropenyl group instead of a simple vinyl group did not afford the ring expansion product but produced bicyclo[5.4.0]undecane via the ene reaction.     

Photochemistry of 3-Substituted 1-Iminopyridinium Ylides. Regiospecific versus non-regiospecific photoisomerization patterns [1]

3-Substituted 1-iminopyridinium ylides 1 undergo photo-induced ring enlargement to 1H-1,2-diazepines. With strongly electron-withdrawing substituents the ring expansion process is regiospecific and leads exclusively to 4-substituted 1 H-1, 2-diazepines. Weak electron-donating substituents, like a methyl group and halogen atoms, do not have any directing effect since both 4- and 6-substituted 1 H -1,2-diazepines are obtained. With strong electron-donating substituents no diazepines are formed; instead one observes photo-induced isomerization to the 2-aminopyridine derivatives, the process being non-regiospecific. Regiospecific photo-induced ring expansion processes are explained in terms of a simple HMO model.     

Diastereoselective synthesis of (2S,5S)- and (2S,5R)-N-benzyloxycarbonyl-5-hydroxypipecolic acids from trans-4-hydroxy-l-proline

An efficient diastereoselective synthesis of cis- and trans-5-hydroxy-(2S)-N-benzyloxycarbonyl pipecolic acids, starting from trans-4-hydroxy-l-proline is described. The key synthetic strategies involve the regioisomeric ring expansion of keto ester 8 and diastereoselective reduction of ketone 11 in high selectivity and yield.