Intra- vs. intermolecular hydrogen bonding: dimers of alpha-hydroxyesters with methanol

Intermolecular hydrogen bonding competes with an intramolecular hydrogen bond when methanol binds to an alpha-hydroxyester. Disruption of the intramolecular OH...O=C contact in favour of a cooperative OH...OH...O=C sequence is evidenced by FTIR spectroscopy for the addition of methanol to the esters methyl glycolate, methyl lactate and methyl alpha-hydroxyisobutyrate in seeded supersonic jet expansions. Comparison of the OH stretching modes with quantum-chemical harmonic frequency calculations and 18O labelling of methanol unambiguously prove the insertion of methanol into the intramolecular hydrogen bond. This is in marked contrast to UV/IR hole burning studies of the homologous system methyl lactate: (+/-)-2-naphthyl-1-ethanol, where only addition complexes were found and the intramolecular hydrogen bond was conserved. This switch in hydrogen bond pattern from aliphatic to aromatic heterodimers is thought to reflect not only a kinetic propensity but also a thermodynamic preference for addition complexes when dispersion forces become more important in aromatic systems.     

Sulfoxide-controlled S(N)2' displacements between cyanocuprates and epoxy vinyl sulfoxides

Two short and convergent routes have been devised for the preparation of enantiomerically pure acyclic epoxy vinyl sulfoxides. These substrates undergo highly regio- and stereoselective S(N)2' displacements with lithium cyanocuprates to give alpha'-alkylated, gamma-oxygenated Z alpha,beta-unsaturated sulfoxides in moderate to good yields and with good to excellent diastereoselectivities. The absolute configuration of the newly formed carbon-carbon bond is primarily controlled by the chiral sulfur atom, which in a nonreinforcing situation can override the intrinsic anti tendency of the vinyl oxirane moiety and forces the cuprate to undergo syn addition. The hydroxy vinyl sulfoxide functionality of the resulting adducts should allow for subsequent asymmetric transformations thus enhancing the synthetic usefulness of this methodology.     

Chiral discrimination in lithium complexes of bis(5H-pyrroles) and bis(oxazolines)

The 1:1 and 2:1 complexes of chiral bis(5H-pyrroles) and bis(oxazolines) with the lithium cation have been studied by means of DFT methods (B3LYP/6-31G and B3LYP/6-311+G). The energetic, geometric, electronic, and orbital properties of the complexes have been analyzed. The chiral discrimination in the 2:1 complexes (homo vs heterochiral ones) indicate that in all the cases the heterochiral complexes are more stable than the homochiral ones, except for the tert-butyl derivatives. The chiral discrimination energies will be discussed on the basis of different parameters related to the lithium atom such as the N-Li distance, the orbital interaction between the lone pair of the nitrogen and an empty orbital of the lithium, and its atomic contribution to the total energy of the complexes.     

Chiral recognition between 1-(4-fluorophenyl)ethanol and 2-butanol: higher binding energy of homochiral complexes in the gas phase

Diastereomeric adducts between (S)-1-(4-fluorophenyl)-ethanol and R and S 2-butanol, formed by supersonic expansion, have been investigated by means of a combination of mass selected resonant two-photon ionization-spectroscopy and infrared depletion spectroscopy. Chiral recognition is evidenced by the specific spectroscopic signatures of the S(1)← S(0) electronic transition as well as different frequencies and intensities of the OH stretch vibrational mode in the ground state. D-DFT calculations have been performed to assist in the analysis of the spectra and the determination of the structures. The homochiral and heterochiral complexes show slight structural differences, in particular in the interaction of the alkyl groups of 2-butanol with the aromatic ring. The experimental results show that the homochiral [FE(S)·B(S)] complex is more stable than the heterochiral [FE(S)·B(R)] diastereomer in both the ground and excited states. The binding energy difference has been evaluated to be greater than 0.60 kcal mol(-1).     

Structural,luminescence, and NMR studies of the reversible binding of acetate,lactate, citrate,and selected amino acids to chiral diaqua ytterbium,gadolinium, and europium complexes

The nature of the ternary complexes formed in aqueous media at ambient pH on reversible binding of acetate, lactate, citrate, and selected amino acids and peptides to chiral diaqua europium, gadolinium, or ytterbium cationic complexes has been examined. Crystal structures of the chelated ytterbium acetate and lactate complexes have been defined in which the carboxylate oxygen occupies an "equatorial" site in the nine-coordinate adduct. The zwitterionic adduct of the citrate anion with [EuL1] was similar to the chelated lactate structure, with a 5-ring chelate involving the apical 3-hydroxy group and the alpha-carboxylate. Analysis of Eu and Yb emission CD spectra and lifetimes (H2O and D2O) for each ternary complex, in conjunction with 1H NMR analyses of Eu/Yb systems and 17O NMR and relaxometric studies of the Gd analogues, suggests that carbonate, oxalate, and malonate each form a chelated (q = 0) square-antiprismatic complex in which the dipolar NMR paramagnetic shift (Yb, Eu) and the emission circular polarization (gem for Eu) are primarily determined by the polarizability of the axial ligand. The ternary complexes with hydrogen phosphate, with fluoride, and with Phe, His, and Ser at pH 6 are suggested to be monoaqua systems with Eu/Gd with an apical bound water molecule. However, for the ternary complexes of simple amino acids with [YbL1]3+, the enhanced charge demand favors a chelate structure with the amine N in an apical position. Crystal structures of the Gly and Ser adducts confirm this. In peptides and proteins (e.g. albumin) containing Glu or Asp residues, the more basic side chain carboxylate may chelate to the Ln ion, displacing both waters.     

Synthesis and structural chemistry of alkali metal tris(HMDS) magnesiates containing chiral diamine donor ligands

Six alkali metal tris(HMDS) magnesiate complexes (HMDS, 1,1,1,3,3,3,-hexamethyldisilazide) containing chiral diamine ligands have been prepared and characterised in both the solid- and solution-state. Four of the complexes have a solvent-separated ion pair composition of the form [{M·(chiral diamine)(2)}(+){Mg(HMDS)(3)}(-)] [M = Li for 1 and 3, Na for 2 and 4; chiral diamine = (-)-sparteine for 1 and 2, (R,R)-TMCDA for 3 and 4, (where (R,R)-TMCDA is N,N,N',N'-(1R,2R)-tetramethylcyclohexane-1,2-diamine)] and two have a contacted ion pair composition of the form [{K·chiral diamine}(+){Mg(HMDS)(3)}(-)](n) [chiral diamine = (-)-sparteine for 5 and (R,R)-TMCDA for 6]. In the solid-state, complexes 1-4 are essentially isostructural, with the lithium or sodium cation sequestered by the respective chiral diamine and the previously reported anion consisting of three HMDS ligands coordinated to a magnesium centre. As such, complexes 1-4 are the first structurally characterised complexes in which the alkali metal is sequestered by two molecules of either of the chiral diamines (-)-sparteine (1 and 2) or (R,R)-TMCDA (3 and 4). In addition, complex 4 is a rare (R,R)-TMCDA adduct of sodium. In the solid state, complexes 5 and 6 exist as polymeric arrays of dimeric [{K·chiral diamine}(+){Mg(HMDS)(3)}(-)](2) subunits, with 5 adopting a two-dimensional net arrangement and 6 a linear arrangement. As such, complexes 5 and 6 appear to be the only structurally characterised complexes in which the chiral diamines (-)-sparteine (5) or (R,R)-TMCDA (6) have been incorporated within a polymeric framework. In addition, prior to this work, no (-)-sparteine or (R,R)-TMCDA adducts of potassium had been reported.     

Visualizing diastereomeric interactions of chiral amine-chiral copper salen adducts by EPR spectroscopy and DFT

Single enantiomers of R/S-methylbenzylamine (MBA) were found to selectively form adducts with two chiral Cu-salen complexes, [Cu(II)(1)] (H(2)1 = N,N'-bis(3,5-ditert-butylsalicylidene)-1,2-diaminocyclohexane) and [Cu(II)(2)] (H(2)2 = N,N'-bis-salicylidene-1,2-cyclohexanediamino). The axial g/A spin Hamiltonian parameters of the Cu-MBA adducts were typical of 5-coordinate species. Enantiomer discrimination in the MBA binding was directly evidenced by W-band CW EPR, revealing an 86 ± 5% preference for formation of the R,R-[Cu(1)] + S-MBA adducts compared to R,R-[Cu(1)] + R-MBA; this was reduced to a 57 ± 5% preference for R,R-[Cu(2)] + S-MBA following removal of the tert-butyl groups. The structure of these diastereomeric adducts was further probed by different hyperfine techniques (ENDOR and HYSCORE), although no structural differences were detected between these adducts using these techniques. The diastereomeric adducts were found to possess lower symmetry, as evidenced by rhombic g tensors and inequivalent H(imine) couplings. This was caused by the selective binding mode of MBA onto one side of the chiral Cu(II) complex. DFT calculations were performed on the R,R-[Cu(1)] + S-MBA and R,R-[Cu(1)] + R-MBA adducts. A distinct difference in orientation and binding mode of the MBA was identified in both adducts, confirming the experimental results. The preferred heterochiral R,R-[Cu(1)] + S-MBA adduct was found to be 5 kJ mol(-1) lower in energy compared to the homochiral adduct. A delicate balance of steric repulsion between the α-proton (attached to the asymmetric carbon atom) of MBA and the methine proton (attached to the asymmetric carbon atom) of [Cu(1)] was crucial in the stereoselective binding.     

Complexing between copper(II) and bulky substituted 3-benzoyl thioureas in copper(II) hexacyanoferrate(II) gelatin-immobilized matrix systems

A novel route to complexes of CuII with various bulky substituted 3-benzoylthioureas: [(1-(2-hydroxy)phenyl-, 1-(4-hydroxy)phenyl-, 1,1-dibenzyl-, 1-methyl-1-phenyl-, 1-N-pentamethylene-] and 1-N-3-oxatetramethylene-3-benzoylthiourea, complexed to a CuII hexacyanoferrate- (II) gelatin-immobilized matrix in contact with aqueous alkali (pH 12.0) solutions of the ligands indicated, has been developed. Under the conditions specified, coordination of each ligand is preceded by decomposition of CuII-hexacyanoferrate(II) to give polymeric copper(II) hydroxide under the influence of OH– ions. With CuII-1-(4-hydroxy)phenyl-3-benzoylthiourea, three different water-insoluble coordination compounds are formed; in the other CuII-ligand systems, two types of complexes are formed, whereas complexing in solution or solid phase in these systems results, as a rule, in the formation of only one coordination compound. In systems such as CuII-1-naphthyl-3-benzoylthiourea, CuII-1-(4-hydroxy-3,5-di-t-butyl)benzyl-3-benzoylthiourea and CuII-1-(4-hydroxy-3,5-di-t-butyl) phenethyl-3-benzoylthiourea, complexing in CuII hexacyanoferrate(II) gelatin-immobilized matrices (GIM) is not observed.     

Chiral rodlike platinum complexes, double helical chains, and potential asymmetric hydrogenation ligand based on "linear" building blocks: 1,8,9,16-tetrahydroxytetraphenylene and 1,8,9,16-tetrakis(diphenylphosphino)tetraphenylene

This paper is concerned with the synthesis of 1,8,9,16-tetrahydroxytetraphenylene (3a) via copper(II)-mediated oxidative coupling, its resolution to optical antipodes, and its conversion to 1,8,9,16-tetrakis(diphenylphosphino)tetraphenylene (3b). On the basis of these chiral "linear" building blocks, three rodlike chiral complexes, triblock (R,R,R,R)-17 and (S,S,S,S)-20 and pentablock (R,R,R,R,R,R,R,R)-22, were constructed. As a hydrogen bond donor, racemic and optically active 3a was allowed to assemble with linear acceptors to afford highly ordered structures. A 1:1 adduct of 4,4'-bipyridyl and (+/-)-3a exists in a dimeric form of 3a linked by 4,4'-bipyridyl through hydrogen bonds. Pyrazine serves as a short linker between achiral parallel chains each formed by (+/-)-3a, while self-assembly of homochiral 3a into alternate parallel chains occurs in the adduct of 5,5'-dipyrimidine with (+/-)-3a. Self-assembly of (S,S)-3a or (R,R)-3a with 4,4'-dipyridyl yielded a packing of chiral double helical chains formed by chiral tetrol 3a molecules. A novel chiral ligand, (S,S)-23, derived from 3a was used in the asymmetric catalytic hydrogenation of alpha-acetamidocinnamate, yielding up to 99.0% ee and 100% conversion.     

Solvent-free synthesis of benzo[a]pyrene 7,8-diol 9,10-epoxide adducts at the N(2)-position of deoxyguanosine

[reaction: see text] The first solid-state (or solvent-free) synthesis of protected deoxyguanosine (dG) adducts of benzo[a]pyrene diol epoxides at room temperature is reported. Whereas dG adducts derived from cis- and trans-opening of (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (DE-1 1) are formed as a 1:1 mixture, the direct opening of the diastereomeric (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (DE-2, 2) produced a 15:85 ratio favoring the trans-opened dG adduct 7.     

erythro-1-Naphthyl-1-(2-piperidyl)methanol: synthesis,resolution, NMR relative configuration,and VCD absolute configuration

The erythro isomer of 1-naphthyl-1-(2-piperidyl)methanol 4, an efficient chiral modifier for asymmetric heterogeneous hydrogenation, was obtained as the major isomer (95%) in two steps while the threo isomer can be obtained as the major isomer (67%) in three steps. erythro-4 and threo-4 were resolved on a CHIRALCEL OD-RH column. It has been shown by VCD that the diastereomer determined as the erythro by NMR was indeed the erythro and that the first eluted (-)-enantiomer on CHIRALCEL OD-R or -RH columns has the (1R,2S) configuration. The VCD studies identify the presence of at least five conformers in CDCl(3) solution. Moreover, this (-)-(1R,2S) absolute configuration found by VCD is consistent with the expected stereo-outcome of catalytic hydrogenation of pyruvate into lactate, which supported the (+)-(1S,2R) assignment.     

Development of a novel synthetic method for ring construction using organometallic complexes and its application to the total syntheses of natural products

Organometallic complexes are useful tools in synthetic organic chemistry. We investigated a novel synthetic method for ring construction using organometallic complexes and synthesized natural products and biologically active substances using these methods. Metalacycles formed from an early transition metal and diene, enyne, and diyne are stable under the reaction conditions and they are easily converted into compounds with functional groups by the addition of various agents. We have developed a novel synthetic method of heterocycles from enyne and diene using Cp2ZrBu2. The total syntheses of (-)-dendrobine, (+/-)-mecembrane, and (+/-)-mecembrine were achieved using this procedure. To synthesize these natural products as a chiral form, a novel palladium-catalyzed asymmetric allylic amination was developed, and chiral 2-arylcyclohexenylamine derivatives were synthesized. From these compounds, the total syntheses of (-)-mesembrane, (-)-mesembrine, (+)-crinamine, (-)-haemanthidine, and (+)-pretazetine were achieved. By further development of this procedure, a chiral 2-siloxymethylcyclohexenylamine derivative could be synthesized and the novel synthesis of indole derivatives was developed from this compound. From this indole derivative, (-)-tsubifoline and (-)-strychnine were synthesized.     

Synthesis, solid-state structures, and aggregation motifs of phosphines and phosphine oxides bearing one 2-pyridone ring

Three phosphines and their corresponding oxides bearing one 2-pyridone ring and two benzene rings were synthesized. Their single-crystal X-ray analyses exhibited three kinds of molecular aggregation: bimolecular aggregates, chiral one-dimensional structures, and achiral one-dimensional structures. In the bimolecular aggregate of (2-oxo-1, 2-dihydro-x-pyridyl)diphenylphosphines (x = 3: 2a and 6: 2c), cyclic dimers that are derived from two 2-pyridone rings are observed. In contrast, (2-oxo-1,2-dihydro-5-pyridyl)diphenylphosphine (2b) molecules form a chiral one-dimensional chain via intermolecular hydrogen bonding. In the case of phosphine oxides, their oxygen always acts as a hydrogen acceptor of the hydrogen bonding. Thus, (2-oxo-1,2-dihydro-x-pyridyl)diphenylphosphine oxides (x = 3: 3a and 5: 3b) form hydrogen bonds intermolecularly between the oxygen atom on the phosphoryl group and the hydrogen atom on nitrogen to construct a chiral or an achiral one-dimensional chain. Interestingly, (2-oxo-1,2-dihydro-6-pyridyl)diphenylphosphine oxide (3c) exists as a 2-hydroxypyridine form (enol form) in a crystalline state, and intermolecular hydrogen bonds between the phosphoryl oxygen and the hydroxy proton construct an achiral one-dimensional chain.     

Structural scaffold of 18-crown-6 tetracarboxylic acid for optical resolution of chiral amino acid: X-ray crystal analyses and energy calculations of complexes of D- and L-isomers of tyrosine, isoleucine, methionine and phenylglycine

To clarify the structural scaffold of (+)-18-crown-6 tetracarboxylic acid ((+)-18C6H4) for the optical resolution of a chiral amino acid, the crystal structures of its equimolar complexes with L- and D-isomers of tyrosine (Tyr), isoleucine (Ile), methionine (Met) and phenylglycine (PheG) were analysed by X-ray diffraction methods. (+)-18C6H4 took very similar conformations for all complexes. Although the chemical structure of (+)-18C6H4 is C2-symmetric, it took a similar asymmetric ring conformation of radius ca. 6.0 A. In all complexes, the amino group of chiral amino acids was located near the center of the ring and formed three hydrogen bonds and five electrostatic interactions with eight oxygen atoms of the ether ring and carboxyl groups. Also, the Calpha atom of chiral amino acids participated in Calpha-H...O interaction with the oxygen atom of (+)-18C6H4. In contrast, the carboxyl group of chiral amino acids did not directly interact with (+)-18C6H4. These results indicate that the structural scaffold of (+)-18C6H4 for the optical resolution of chiral amino acids is mainly based on the mode of interaction of (+)-18C6H4 with the amino and Calpha-H groups of chiral amino acids. The differences in interaction pattern and binding energy between the L- and D-isomers of each amino acid are discussed in relation to the chiral recognition of (+)-18C6H4.     

Fe(II) mononuclear complexes with a new aminopyridyl ligand bearing a pivaloylamido arm. Preparation and spectroscopic characterizations of a Fe(III)-hydroperoxo complex with oxygen and nitrogen donors

Two new mononuclear FeII complexes, [(L52aH)FeII](PF6)2 (1-(PF6)2) and [(L52a)FeII]BPh4 (2-(BPh4)) have been synthesized with the new aminopyridyl ligand bearing a pivaloylamido arm L52aH (2,2-dimethyl-N-[6-({[2-(methyl-pyridin-2-ylmethyl-amino)-ethyl]-pyridin-2-ylmethyl-amino}-methyl)-pyridin-2-yl]-propionamide), or its deprotonated form L52a-. The structures of the ferrous complexes have been determined by X-ray analysis. The mononuclear FeII is in a pseudo-octahedral environment in both complexes, the six positions around the metal center being occupied by five nitrogen atoms and one oxygen atom from the ligand. Whatever the protonation state of the amide function, the structures are very similar, the FeII being 6-fold coordinated by the two amines, three pyridines, and the oxygen atom from the ligand. These two complexes exhibit an acid/base equilibrium in solution that has been studied by UV-vis spectroscopy and cyclic voltammetry in acetonitrile. The reactivity of 1-(PF6)2 with H2O2 in methanol affords the formation of a new low-spin FeIII(OOH) intermediate in which the oxygen atom is retained in the coordination sphere of the metal.     

Synthesis and application of chiral phosphino-imidazoline ligands: Ir-catalyzed enantioselective hydrogenation

[reaction: see text] A series of chiral phosphino-imidazolines (PHIM ligands) 1a-j with different substituents at the stereogenic center, the nitrogen atom of the imidazoline ring, and at the phosphorus atom were synthesized. Iridium complexes derived from these ligands have been evaluated as catalysts for the enantioselective hydrogenation of unfunctionalized olefins. In several cases, higher enantiomeric excesses were observed than with analogous phosphino-oxazoline ligands.     

NMR relaxometric study of new Gd(III) macrocyclic complexes and their interaction with human serum albumin

Five novel Gd(iii) complexes based on the structure of the heptadentate macrocyclic 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) ligand have been synthesized and their (1)H and (17)O NMR relaxometric properties investigated in detail. The complexes have been functionalised on the secondary nitrogen atom of the macrocyclic ring with different pendant groups for promoting their ability to interact non-covalently with human serum albumin (HSA). The analysis of the proton relaxivity, measured as a function of pH and magnetic field strength, have revealed that the three complexes bearing a poly(ethylene glycol)(PEG) chain possess a single coordinated water molecule, whereas the complexes functionalised with 1-[3-(2-hydroxyphenyl)]-propyl and 1-[3-(2-carboxyphenyloxy)]-propyl pendant groups have two inner sphere water molecules. The water exchange rates, measured by variable temperature (17)O NMR, cover a broad range of values (from 18 to 770 ns) as a function of their charge, the chemical nature of the substituent and its ability to organize a second sphere of hydration near the water(s) binding site. All the complexes have shown some degree of interaction with HSA, with a stronger binding affinity measured for those bearing an aromatic moiety on the pendant group. However, upon binding the expected relaxation enhancement has not been observed and this has been explained with the displacement of the coordinated water molecules by the protein and formation of ternary adducts.     

Vicinal stereocontrol during nucleophilic addition to arene chromium tricarbonyl complexes: formal synthesis of (+/-)-erythro Juvabione

[reaction: see text] Vicinal stereocontrol during nucleophilic addition of tert-butyl lithiopropionate to eta(6)-anisole chromium tricarbonyl complexes with differing para substituents has been studied. Excellent vicinal double stereoinduction (>99:1) was observed when the para substituent was Si(CH(3))(3), and this has been applied to a stereoselective formal synthesis of (+/-)-erythro Juvabione. Asymmetric synthesis by chiral auxiliary directed nucleophilic addition is also discussed.     

Synthesis of lateral macrobicyclic compartmental ligands: structural,magnetic, electrochemical,and catalytic studies of mono- and binuclear copper(II) complexes

A series of putative mono- and binuclear copper(II) complexes, of general formulas [CuL](ClO(4)) and [Cu(2)L](ClO(4))(2), respectively, have been synthesized from lateral macrocyclic ligands that have different compartments, originated from their corresponding precursor compounds (PC-1, 3,4:9,10-dibenzo-1,12-[N,N'-bis[(3-formyl-2-hydroxy-5-methyl)benzyl]diaza]-5,8-dioxacyclotetradecane; and PC-2, 3,4:9,10-dibenzo-1,12-[N,N'-bis[(3-formyl-2-hydroxy-5-methyl)benzyl]diaza]-5,8-dioxacyclopentadecane). The precursor compound PC-1 crystallized in the triclinic system with space group P(-)1. The mononuclear copper(II) complex [CuL(1a)](ClO(4)) is crystallized in the monoclinic system with space group P2(1)/c. The binuclear copper(II) complex [Cu(2)L(2c)](ClO(4))(2) is crystallized in the triclinic system with space group P(-)1; the two Cu ions have two different geometries. Electrochemical studies evidenced that one quasi-reversible reduction wave (E(pc) = -0.78 to -0.87 V) for mononuclear complexes and two quasi-reversible one-electron-transfer reduction waves (E(1)(pc) = -0.83 to -0.92 V, E(2)(pc) = -1.07 to -1.38 V) for binuclear complexes are obtained in the cathodic region. Room-temperature magnetic-moment studies convey the presence of antiferromagnetic coupling in binuclear complexes [mu(eff) = (1.45-1.55)mu(B)], which is also suggested from the broad ESR spectra with g = 2.10-2.11, whereas mononuclear complexes show hyperfine splitting in ESR spectra and they have magnetic-moment values that are similar to the spin-only value [mu(eff) = (1.69-1.72)mu(B)]. Variable-temperature magnetic susceptibility study of the complex shows that the observed -2J value for the binuclear complex [Cu(2)L(1b)](ClO(4))(2) is 214 cm(-1). The observed initial rate-constant values of catechol oxidation, using complexes as catalysts, range from 4.89 x 10(-3) to 5.32 x 10(-2) min(-1) and the values are found to be higher for binuclear complexes than for the corresponding mononuclear complexes.     

Remarkable control of radical cyclization processes of cyclic enyne: total syntheses of (+/-)-methyl gummiferolate, (+/-)-methyl 7beta-hydroxykaurenoate, and (+/-)-methyl 7-oxokaurenoate and formal synthesis of (+/-)-gibberellin a(12) from a common synthetic precursor.

Total syntheses of (+/-)-methyl gummiferolate (13b), (+/-)-methyl 7beta-hydroxykaurenoate (14b), and (+/-)-methyl 7-oxokaurenoate (14d) and a formal synthesis of (+/-)-gibberellin A(12) (15) have been accomplished through the common synthetic precursor, (3aR,7aR)-3,3-dimethyl-7a-(2-propynyl)-3a,4,7,7a-tetrahydroisobenzofuranone (16). The homoallyl-homoallyl radical rearrangement reaction of the monocyclic enyne 25, derived from 16 in two steps, afforded the bicyclo[2.2.2]octane compound 26, which was converted to (+/-)-methyl gummiferolate (13b). In contrast, the radical cyclization of the bicyclic enyne 16 gave the tricyclic lactone 19, leading to (+/-)-methyl 7beta-hydroxykaurenoate (14b) and (+/-)-methyl 7-oxokaurenoate (14d). Transformation of 14d into lactone 20 was carried out in a single step under bromination conditions. This constitutes a formal total synthesis of gibberellin A(12) (15).