Manuel Arnó

Understanding the Participation of Quadricyclane as Nucleophile in Polar [2σ + 2σ + 2π] Cycloadditions toward Electrophilic π Molecules

The formal [2sigma + 2sigma + 2pi] cycloaddition of quadricyclane, 1, with dimethyl azodicarboxylate, 2, in water has been studied using DFT methods at the B3LYP/6-31G** and MPWB1K/6-31G** levels. In the gas phase, the reaction of 1 with 2 has a two-stage mechanism with a large polar character and an activation barrier of 23.2 kcal/mol. Inclusion of water through a combined discrete-continuum model changes the mechanism to a two-step model where the first nucleophilic attack of 1 to 2 is the rate-limiting step with an activation barrier of 14.7 kcal/mol. Analysis of the electronic structure of the transition state structures points out the large zwitterionic character of these species. A DFT analysis of the global electrophilicity and nucleophilicity of the reagents provides a sound explanation about the participation of 1 as a nucleophile in these cycloadditions. This behavior is reinforced by a further study of the reaction of 1 with 1,1-dicyanoethylene.

Synthesis of (+)-podocarp-8(14)-en-13-one and methyl-(+)-13-oxo-podocarp-8(14)-en-18-oate from abietic acid

Abstract An efficient method for the preparation of (+)-podocarp-8(14)-en-13-one 6 and methyl-(+)-13-oxo-podocarp-8(14)-en-18-oate 8 from abietic acid is described.

Understanding the cooperative NHC/LA catalysis for stereoselective annulation reactions with homoenolates. A DFT study

The role of Ti(Oi-Pr)(4) Lewis acid (LA) in the cooperative N-heterocyclic carbene (NHC)/LA catalyzed addition of enals to enones to yield cis-cyclopentenes has been investigated using DFT methods at the B3LYP/6-31G** computational level. Ti(IV) effectively catalyzes the reaction by formation of a complex with cinnamaldehyde 1, which favors the nucleophilic attack of NHC 5 on 1, and the subsequent proton abstraction to yield the extended Ti(IV)-Breslow intermediate 21. The nature of the metal involved in the LA catalyst plays a relevant role due to the more basic character of NHCs than aldehydes. Thus, strong LAs, such as Zn(OTf)(2), prevent the catalytic behavior of NHCs to form a very stable complex. The subsequent formation of a complex between chalcone 2 and the extended Ti(IV)-Breslow intermediate 21 favors the cis stereoselective C-C bond-formation. Analysis of the structures of Ti(IV)-complex precursors for the cis and trans C-C bond-formation steps allows for an explanation of the unexpected cis stereoselectivity.

Controlled rearrangement of lactam-tethered allenols with brominating reagents: a combined experimental and theoretical study on α- versus β-keto lactam formation.

N-Bromosuccinimide (NBS) smoothly promotes the ring expansion of lactam-tethered allenols to efficiently afford cyclic α- or β-ketoamides with good yields and high chemo-, regio-, and diastereoselectivity, through controlled C-C bond cleavage of the β- or γ-lactam nucleus. Interestingly, in contrast to the rearrangement reactions of 2-azetidinone-tethered allenols, which lead to the corresponding tetramic acid derivatives (β-keto lactam adducts) as the sole products, the reactions of 2-indolinone-tethered allenols under similar conditions give quinoline-2,3-diones (α-keto lactam adducts) as the exclusive or major products. To rationalize the experimental observations, theoretical studies have been performed.

Understanding the Mechanism of the Intramolecular Stetter Reaction. A DFT Study

The mechanism of the N-heterocyclic carbene (NHC)-catalyzed intramolecular Stetter reaction of salicylaldehyde 1 to yield chromanone 3 has been theoretically studied at the B3LYP/6-31G** level. This NHC-catalyzed reaction takes place through six elementary steps, which involve: (i) formation of the Breslow intermediate IN2; (ii) an intramolecular Michael-Type addition in IN2 to form the new C-C σ bond; and (iii) extrusion of the NHC catalyst from the Michael adduct to yield chromanone 3. Analysis of the relative free energies in toluene indicates that while formation of Breslow intermediate IN2 involves the rate-determining step of the catalytic process, the intramolecular Michael-type addition is the stereoselectivity determining step responsible for the configuration of the stereogenic carbon α to the carbonyl of chromanone 3. An ELF analysis at TSs and intermediates involved in the Michael-type addition allows for the characterization of the electronic changes along the C-C bond-formation.

Synthesis and cytotoxic activity of novel C7-functionalized spongiane diterpenes.

Based on two lead cytotoxic spongiane diterpenes, a new series of C7-oxygenated derivatives were synthesized and evaluated for their antitumor activity in vitro against the cancer cell lines HeLa and HEp-2. In general, introduction of either hydroxyl or acetoxy groups at C-7 did not improve the resultant cytotoxicity, while the presence of a butyrate ester led to more active compounds (CC(50)=4.0-9.5 microM).

DFT study of the molecular mechanism of Lewis acid induced [4 + 3] cycloadditions of 2-alkylacroleins with cyclopentadiene.

The mechanism of the Lewis acid (AlCl(3)) induced [4 + 3] cycloaddition of 2-methylacrolein with cyclopentadiene (Cp) [ J. Am. Chem. Soc. 2004, 126, 2692] has been examined here through DFT calculations at the MPW1K(DCM)/6-31+G** level. Formation of these seven-membered carbocycles is a domino process that comprises three consecutive reactions. The first one is a polar Diels-Alder reaction that is initialized by the nucleophilic attack of Cp to the beta-conjugated position of acrolein, yielding the formation of the endo and exo [4 + 2] cycloadducts. The corresponding LA-[4 + 2] cycloadduct complexes equilibrate through a skeleton rearrangement with a low free activation energy with two seven-membered zwitterionic intermediates, which undergo a rapid intramolecular hydride shift to yield irreversibly the formally endo and exo [4 + 3] cycloadducts. A comparative analysis of this mechanism with that for the Lewis acid induced [4 + 3] cycloadditions of 2-silyloxyacroleins allows establishment of the requirements for the formation of the seven-membered carbocycles.

Diastereoselective synthesis of spongian diterpenes. Total synthesis of the furanoditerpene (−)-spongia-13(16),14-diene

Abstract An effective diastereoselective synthesis of the marine-sponge metabolite (−)-spongia-13(16),14-diene 1 is achieved starting from S-(+)-carvone via a homochiral phenanthrenone as the key intermediate for the construction of the furan ring system. S-(+)-Carvone was transformed into the phenanthrenone 2a in six steps (53% overall yield), using an intramolecular Diels-Alder reaction as the key step. Conversion of the enone function in 2a into an epoxyaldehyde function followed by cyclisation and aromatisation in acid conditions completed the construction of ring D.

Spongian pentacyclic diterpenes. Stereoselective synthesis of aplyroseol-1, aplyroseol-2 and deacetylaplyroseol-2

Natural spongian pentacyclic diterpenes aplyroseol-1 19, aplyroseol-2 18 and deacetylaplyroseol-2 17 have been synthesized in enantiomerically pure form from (+)-podacarp-8(14)-en-13-one 3. Key intermediate in these syntheses is a suitably substituted acid-dialdehyde 2, which is prepared from enone 3 by a sequence of transformations involving stereoselective introduction of a C-7 oxygen functionality, photoaddition of acetylene to the C(8)–C(14) double bond to form a cyclobutene ring system, reductive cyanation of the C-13 carbonyl group, hydrolysis of the resulting nitrile group, and ozonolysis of the cyclobutene moiety. An intramolecular participation of the 7α-hydroxy group in the hydrolysis of the 13α-nitrile 8 is set in focus.

SESQUITERPENE LACTONES AND ACETYLENES FROM ARTEMISIA REPTANS

Abstract The aerial parts of Artemisia reptans yielded a new thiophene acetylene, four new guaianolides, a new acyclic sesquiterpene related to davanone and several known compounds.