Face selectivity in the reactions of 2,4-disubstituted adamantanes and their modification by inclusion in β-cyclodextrin solutions

Sodium borohydride reduction reactions on 4-X-adamantan-2-ones (where X=ethyleneketal 11, ethylenethioketal 12, and methylene 15) were studied, which gave Z-alcohols 16 and 17 (from en-face attack) as the predominant products for ketones 11 and 12, but gave 1:1 mixture of Z- and E-18 alcohols for ketone 15. The en/zu face selectivity of 15 in sodium borohydride reduction was enhanced to 32/68 in β-CD solution. Both 1,3-dipolar addition and dichlorocarbene addition reactions on 4-ethyleneketal-2-methyleneadamantane 13 underwent again predominant en-face attack to give products in an E/Z ratio of >99:1 and 92:8, respectively. The exceptional high zu-face selectivity on the dichlorocarbene addition reaction of 15 may be explained by a temporal complexation between the carbene and the C₄-oxo group. In the epoxidation reaction of 13 and 15 the zu-face attack products were favored despite their steric congestions suggesting that hydrogen bonding interaction between the peroxide reagent and the C₄-oxo or 4-ethyleneketal is involved.     

New route to alkylaluminum hydroxides via hydrolysis of cyclopentadienylaluminum complexes

A novel, very simple and effective synthetic method for the formation of alkylaluminum complexes with terminal hydroxy group via hydrolysis of cyclopentadienylaluminum compounds has been found. Investigations of the hydrolysis of cyclopentadienylaluminum complexes (L)Al(Me)Cp (1) and (L)Al(Et)Cp (2) (L = HC[(CMe)(2,6-ⁱPr₂C₆ H₃N)]₂) have shown that the reaction leads to the formation of (L)Al(Me)OH (3) and (L)Al(Et)OH (4), respectively. The high selectivity of the hydrolysis was revealed. The crystal structures of 1, 2 and 4 were determined.     

Investigation of the selective reduction of isatin derivatives. Synthesis of α-hydroxyacetophenone derivatives and ethyl spiro-3,3-(ethylenedioxy)-2-hydroxyindoline carboxylates

The product from the reduction of ethyl spiro-3,3-(ethylenedioxy)-2-oxindole carboxylates (1) using borohydride salts has been found to be dependant upon both solvent and metal ion. With polar solvents and lithium bromide/sodium borohydride, spiro-3,3-(ethylenedioxy)-2-hydroxyindole carboxylates (2) are obtained in high yields whilst [2-(2-hydroxymethyl-[1,3]dioxolan-2-yl)-phenyl]-carbamic acid ethyl esters (3) are obtained using sodium borohydride in less polar solvents.     

Chemo- and diastereoselective control for a flexible approach to (5S,6S)-6-alkyl-5-benzyloxy-2-piperidinones

Chemo- and diastereoselective transformation of the N,O-acetals and their chain tautomers (4/5), readily derived from protected 3-hydroxyglutarimide 1a, was studied. It was uncovered that while the reaction with a combination of boron trifluoride etherate/zinc borohydride led to cyclic products (5S,6S/R)-6-alkyl-5-benzyloxy-2-piperidinones 3/2, and 6 in modest chemo- and diastereoselectivities, the reaction of 4/5 with zinc borohydride led exclusively to the formation of the ring-opening products 6 in excellent anti-diastereoselectivities. On the basis of the latter reaction, a flexible approach to (5S,6S)-6-alkyl-5-benzyloxy-2-piperidinones 3 was disclosed.     

An easy ABD→ABCD strategy to indolo[2,3-a]quinolizin-4-one. Synthesis of deplancheine and yohimbane

The efficient synthesis of indolo[2,3-a]quinolizin-4-ones 2 is described in two steps via formal [3+3] cycloaddition reaction of α-sulfonyl tryptaminylacetamide 4 with various α,β-unsaturated esters 5 and the regioselective reduction of the resulting glutarimides 3 with sodium borohydride then sequent further dehydrated cyclization in the presence of boron trifluoride etherate. The useful building block is applied to synthesize deplancheine (1a) and yohimbane (1b).     

Reductive ring opening of dihydrodibenzothiepine and dihydrodinaphtho-oxepine and -thiepine

The 4,4′di-tert-butylbiphenyl (DTBB)-catalysed lithiation of dihydrodibenzothiepine (1) at −78 °C for 30 min followed by reaction with a carbonyl compound [^tBuCHO, Ph(CH₂)₂CHO, PhCHO, (n-C₅H₁₁)₂CO, (CH₂)₅CO, (CH₂)₇CO, (−)-menthone] at the same temperature leads, after hydrolysis with 3 M hydrochloric acid, to sulphanyl alcohols 2. If after addition of a carbonyl compound as the first electrophile [Me₂CO, (CH₂)₅CO, (−)-menthone], the resulting dianion of type II is allowed to react at room temperature for 30 min, a second lithiation takes place to give an intermediate of type III, which by reaction with a second electrophile [Me₂CO, Et₂CO, (CH₂)₅CO, ClCO₂Et], yields, after hydrolysis, difunctionalised byphenyls 4. The cyclisation of the sulphanyl alcohol 2c under acidic conditions yields the eight-membered sulphur containing heterocycle 3. The lithiation of dihydrodinaphthoheteroepines 7 and 10 with 2.2 equiv of lithium naphthalenide in THF at −78 °C followed by reaction with different electrophiles [H₂O, D₂O, ^tBuCHO, Me₂CO, Et₂CO, (CH₂)₄CO, (CH₂)₅CO] at the same temperature leads, after hydrolysis, to unsymmetrically 2,2′-disubstituted binaphthyls 9 and 12, respectively. When the lithiation is performed with an excess of lithium in the presence of a catalytic amount of DTBB (10% molar), a double reductive cleavage takes place to give the dianionic intermediate VII, which by reaction with different electrophiles [H₂O, Me₂CO, Et₂CO, (CH₂)₄CO, (CH₂)₅CO], followed by hydrolysis with water, yields symmetrically 2,2′-disubstituted binaphthyls 8 and 11. In the case of starting from (R)- or (S)-dihydrodinaphthoheteroepines 7 and 10, these methodologies allow us to prepare enantiomerically pure compounds 8, 11 and 12.     

Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo(2R)-1a alcohol. The endo(2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C₂ symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH₄ reduction of acetophenone. The C₂ symmetry appears to play a fundamental role.     

Di- and tetracarboxylate ligands for highly luminescent terbium(III) complexes on the basis of sulfonylcalix[4]arene scaffold

New di- (2) and tetracarboxylate ligands (4) were prepared on a sulfonylcalix[4]arene platform by O-alkylation of thiacalix[4]arene with ethyl bromoacetate, followed by hydrolysis of the ester function and oxidation of the sulfide bridges. The sulfonyl-based ligands 2 and 4 formed luminescent 1:1 complexes with terbium(III) ion having higher luminescent quantum yield (Φ = 0.29₁ and 0.28₇, respectively) than 1:1 complexes of the corresponding thiacalix[4]arene-based di- (1) and tetracarboxylate ligands (3) (Φ = 0.03₈ and 0.00₃, respectively), implying higher efficiency of sulfonyl ligands (2 and 4) than those of thia ligands (1 and 3) in the energy transfer process.     

Synthesis, properties and complexation of (pS)-1-isocyano-2-methylferrocene, the first planar-chiral isocyanide ligand

Reaction of enantiomerically pure, planar-chiral (_pS)-1-bromo-2-methylferrocene (1) with phthalimide in the presence of Cu₂O produces (_pS)-1-phthalimido-2-methylferrocene (2), quantitative reduction of which with hydrazine hydrate affords (_pS)-1-amino-2-methylferrocene (3) with >99% ee. Formylation of amine 3 followed by dehydration of the resulting (_pS)-1-formamido-2-methylferrocene (4) provides (_pS)-1-isocyano-2-methylferrocene (5), the first example of a planar-chiral isocyanide ligand, in a good yield. Isocyanide 5 reacts with PdI₂ to give the crystallographically characterized chiral complex trans-[PdI₂{(_pS)-1-isocyano-2-methylferrocene}₂] (6). The redox behavior of 4, 5, and 6, accessed by cyclic voltammetry, is discussed.     

β,β-Difluoro analogs of α-oxo-β-phenylpropionic acid and phenylalanine

A simple three-step procedure converted the readily accessible (2-bromo-1,1-difluoroethyl)arenes (2) into α-aryl-α,α-difluoroacetaldehydes (1). Subsequent hydrocyanation, hydrolysis, oxidation and again hydrolysis afforded β-aryl-β,β-difluoro-α-oxopropionic acids (3). Reductive amination transformed the oxoacids 3 into a separable mixture of α-hydroxyacids 11 and racemic β,β-difluoro-β-phenylalanine derivatives (4). Enantiomerically pure β,β-difluorophenylalanine (l-4a) was obtained when α,α-difluoro-α-phenylacet-aldehyde (1a) was condensed with homochiral 1-phenylethylamine, hydrogen cyanide added to the resulting imine, the diastereomeric mixture thus produced hydrolyzed to the carboxamides (15) which were found to be separable by fractional crystallization or chromatography. The pK_a values of the β-aryl-β,β-difluoroalanines (4) were measured and biological profile of the latter probed. 3-(4-Chlorophenyl)-3,3-difluoro-2-oxopropionic acid (4c) proved to be a potent (K_i 27 μM) and selective inhibitor of arogenate dehydratase, a key enzyme catalyzing the last step of the phenylalanine biosynthesis.     

Short-step syntheses and complexation properties of Z,Z-tribenzodidehydro- and all-Z-tribenzo[12]annulenes

Syntheses of all-Z-tribenzo[12]annulenes (1a-c) and Z,Z-tribenzodidehydro[12]annulenes (2a-c) by the reduction of the corresponding tribenzohexadehydro[12]annulenes 3a-c were carried out using a low valent titanium complex generated from Ti(O-i-Pr)₄ and i-PrMgCl. The unique structure of the first reduction products 2a-c as well as 1a-c was fully characterized. Complexation of these annulenes with silver(I) ions produces the corresponding silver complexes. Among them, the silver complexes of 2a-c exhibit interesting monomer-dimer equilibrium.     

Synthesis and structures of dinuclear iron, molybdenum and tungsten complexes derived from (PhCHCHPh)-coupled bis(cyclopentadiene)

Reductive coupling of phenylfulvene with amalgamated calcium metal followed by hydrolysis yields CpPhCHCHPhCp (1) in high yield. Refluxing ligand 1 and Fe(CO)₅ in xylene produces (PhCHCHPh)-coupled bis(cyclopentadienyl) tetracarbonyl diiron (PhCHCHPh)[(η⁵-C₅H₄)Fe(CO)₂]₂ (2) as a mixture of meso (2-meso) and racemic isomers (2-rac). The pure racemic isomers of the Mo and W analogues (3-rac and 4-rac) have been synthesized by lithiation of ligand 1 and addition of (MeCN)₃M(CO)₃ (M = Mo, W) followed by oxidation with 2 equiv. of ferrocenium tetrafluoroborate. All the new complexes have been fully characterized. The molecular structures of 1-meso, 2-meso, 2-rac, 3-rac, and 4-rac have been determined by X-ray diffraction analysis.     

Synthesis of stereopure acyclic 1,5-dimethylalkane chirons: building blocks of highly methyl-branched natural products

An efficient synthetic method towards stereopure acyclic 1,5-dimethylalkane building blocks from methyl (2R)-3-hydroxy-2-methylpropionate (R)-1 (>99% ee) and methyl (2S)-3-hydroxy-2-methylpropionate (S)-1 (>99% ee) through a series of chemical transformations, including Julia–Kocienski olefination and diimide reduction, is described. Through this strategy, two fragments of β-d-mannosyl phosphomycoketide (C₃₂-MPM) and four stereopure 1,5-dimethylalkane C₁₀ chirons are prepared. These C₃₂-MPM fragments and C₁₀ chirons have shown great potential application as building blocks for the synthesis of highly methyl-branched natural products containing chiral oligoisoprenoid-like chains.     

Dimolybdenum complexes containing anions of N,N′-bis(pyrimidine-2-yl)formamidine and N-(2-pyrimidinyl)formamide

The reactions of Mo₂(O₂CCH₃)₄ with different equivalents of N,N′-bis(pyrimidine-2-yl)formamidine (HL1) and N-(2-pyrimidinyl)formamide (HL2) afforded dimolybdenum complexes of the types Mo₂(O₂CCH₃)(L1)₂(L2) (1) trans-Mo₂(L1)₂(L2)₂ (2) cis-Mo₂(L1)₂(L2)₂ (3) and Mo₂(L2)₄ (4). Their UV–Vis and NMR spectra have been recorded and their structures determined by X-ray crystallography. Complexes 2 and 3 establish the first pair of trans and cis forms of dimolybdenum complexes containing formamidinate ligands. The L1 ligands in 1–3 are bridged to the metal centers through two central amine nitrogen atoms, while the L2 ligands in 1–4 are bridged to the metal centers via one pyrimidyl nitrogen atom and the amine nitrogen atom. The Mo–Mo distances of complexes 1 [2.0951(17) Å], 2 [2.103(1) Å] and 3 [2.1017(3) Å], which contain both Mo?N and Mo?O axial interactions, are slightly longer than those of complex 4 [2.0826(12)–2.0866(10) Å] which has only Mo?O interactions.     

(N-Arylaminomethyl)pyridine-N-oxides: Synthesis and characterization of potential ligand systems and the formation of their N,O-chelate aluminum complexes

Pyridine-N-oxide-2-carbaldehyde (4a) was converted to the corresponding imine (5a) by treatment with 2,6-diisopropylaniline. Subsequent reduction with a sodium borohydride gave the corresponding (N-arylaminomethyl)pyridine-N-oxide derivative (6a). A series of analogous compounds was prepared starting from the respective (aldimino)quinoline-N-oxide (4b) or (ketimino)pyridine-N-oxide (10) systems. Deprotonation of the (aminomethyl)pyridine-N-oxides resulted in a series of unexpected reactions, such as coupling, internal redox reactions or fragmentation. Eventually, the N,O-chelate aluminum complexes (22, 23) derived from the (aminoethyl)pyridine-N-oxide ligand systems could be obtained by treatment of the respective iminopyridine-N-oxides with trimethylaluminum. Many products were characterized by X-ray diffraction.     

Synthesis of 1,4-disilacyclohexa-2,5-dienes

Title compounds of the type 2,3,5,6-tetraphenyl-1,4-di-X-1,4-di-Y-1,4-disilacyclohexa-2,5-diene wherein X=Y=NMe₂ (4); X=NMe₂, Y=Cl (cis, trans-5); X=NMe₂, Y=Me [(trans)-6] and X=t-Bu, Y=Cl (trans-8) were synthesized from Si₂(NMe₂)₅Cl, sym-Si₂(NMe₂)₄Cl₂, sym-Si₂(NMe₂)₄Me₂, and sym-Si₂Cl₄(t-Bu)₂, respectively, in the presence of diphenylacetylene at 200 °C. Similarly the analogous title compound from the combination of 1-phenyl-1-propyne and Si₂(NMe₂)₅Cl [X=Y=NMe₂ (cis and trans-7) was synthesized. In all cases where cis/trans diastereomers could arise from two different silicon substituents (5, 6, 8) the trans isomer was the sole or dominant product. Evidence for the intermediacy of the silylene Si(NMe₂)₂ in these reactions was gained from a trapping experiment. Compound 4 upon treatment with SiCl₄, SiBr₄ or PI₃ provided the corresponding 1,1,4,4-tetrahalo derivatives 9a-c, respectively. Treatment of 4 with MeOH or PhOH gave the 1,1,4,4-tetramethoxy and tetraphenoxy analogues 9d and 9e, respectively. The tetrachloro derivative 9a upon LAH reduction led to the corresponding tetrahydro compound 10, while the reaction of 9a with H₂O gave the tetrahydroxy derivative 11. Allowing (trans)-6 to react with SiCl₄ provided a ca. 1:1 cis/trans ratio of the derivative 12 in which X=Cl, Y=Me, and possible pathways that rationalize this loss of stereochemistry are proposed. Synthesis of trans-13 in which X=t-Bu, Y=H was achieved by LAH reduction of 8. All of the title compounds except 8 experience free phenyl rotation at room temperature. At −30 °C this rotation in 8 is essentially halted. The molecular structures of 4, 8, 9c, 9e, 10 and 13 were determined by X-ray crystallography.     

Synthesis of 5-endo-, 5-exo-, 6-endo- and 6-exo-hydroxylated analogues of epibatidine

A convenient, high-yield synthesis of N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one (7) was developed by SmI₂-mediated desulfonylation of 6. Thus, 5-endo-, 5-exo-, 6-endo-, and 6-exo-hydroxylated epibatidine analogues 2a,b and 3a,b were synthesized from 7 by using a Pd(PPh₃)₄-catalyzed reductive Heck coupling reaction and SmI₂-mediated reduction of the carbonyl group as the key steps. Other reaction conditions for the reductive Heck procedure and the reduction step were also investigated.     

Palladium complexes of N-aryl-2-pyridylamines

Palladium complexes of N-phenyl-2-pyridylamine (4) and dipyridylamine substrates (7, 11) have been studied. Due to the coordination ability of the pyridine-nitrogen atoms, the pyridyl substrates, 4, 7, 11 were subjected to Pd(OAc)₂ complexations and a number of N-aryl-2-pyridylamine Pd complexes (13-17) were isolated and characterised, in particular by NMR and ESI-MS. A new method for the preparation of the acetato-bridged six-membered ring palladacycle complex (13) of 4 is reported. The dipyridyl amines 7, 11 formed cis/trans bis-dentate acetato-bridged dimeric Pd₂Lig₂(OAc)₂ (14a,b/16a,b) and Pd₃Lig₂(OAc)₄ complexes (15a,b/17a,b). The N-aryl-2-pyridylamine substrates (4, 7, 11) were prepared by oxidative nucleophilic substitution, by 1,3-cycloaddition reaction or by Buchwald amination.     

Formal total synthesis of aspergillide A

The formal total synthesis of aspergillide A 1 is described. The cross-metathesis of enone 6 with 6-hepten-2-ol derivative 5 provided E-olefin 15 corresponding to the C₄-C₁₄ backbone of 1. The CBS asymmetric reduction of 15 gave allyl alcohol 16, which was transformed into β-alkoxyacrylate 4 which had a formyl group. SmI₂-induced reductive cyclization of 4 gave a 2,6-syn-2,3-trans THP derivative 3 in good yield. After methoxymethylation of 3, the resulting compound 19 was submitted to desilylation and hydrolysis, to afford Fuwa’s key intermediate 2 for the total synthesis of 1.     

Facile syntheses, structural characterizations, and isomerization of disiloxane-1,3-diols

In the hydrolysis reaction of dichlorosilanes having an intramolecular coordinating atom, dcisiloxane-1,3-diols, [(OH){o-(CH₃)₂NCH₂-C₆H₄}RSi]₂O(R=CH₂CH (1), C₆H₅ (2), o-(CH₃)₂NCH₂C₆H₄ (3), Me (4)), were obtained in high yields. The results of the crystal structure analyses of meso-2, rac-2a, rac-2b and 3 are reported. They showed strong intramolecular hydrogen bondings between the hydroxy group and the nitrogen atom. We have also found that the diastereomeric isomerization of meso-2 to rac-2 in CDCl₃ solvent containing moisture occurred to result in the 55:45 equilibrium mixtures of the isomers and vice versa.