Synthesis of 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] and derivatives: precursors of long-chain polyketides

Racemic 1,1′-methylene[(1RS,1′RS,3RS,3′RS,5RS,5′RS)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] ((±)-6) derived from 2,2′-methylenedifuran has been resolved kinetically with Candida cyclindracea lipase-catalysed transesterification giving 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] (−)-6 (30% yield, 98% ee) and 1,1′-methylenedi[(1S,1′S,3S,3′S,5S,5′S)-8-oxabicyclo[3.2.1]oct-6-en-3-yl] diacetate (+)-8, (40% yield, 98% ee). These compounds have been converted into 1,1′-methylenedi[(4S,4′S,6S,6′S)- and (4R,4′R,6R,6′R)-cyclohept-1-en-4,6-diyl] derivatives.     

Polyhydroxylated pyrrolizidines. Part 3: A new and short enantiospecific synthesis of (+)-hyacinthacine A2

(1R,2R,3R,7aR)-1,2-Dihydroxy-3-hydroxymethylpyrrolizidine (+)-Hyacinthacine A₂ 1 has been synthesized by Wittig's methodology using [(2′S,3′R,4′R,5′R)-3′,4′-dibenzyloxy-N-tert-butyloxycarbonyl-5′-tert-butyldiphenylsilyloxymethylpyrrolidin-2′-yl]carbaldehyde 3, prepared from a partially protected DMDP 2, and the appropriated ylide, followed by cyclization by an internal reductive amination process of the resulting unsaturated aldehyde 4 and total deprotection.     

Total, asymmetric synthesis of (1r-1-c-(6′-amino-7′h-purin-8′-yl)-1,4-anhydro-3-azido-2,3-dideoxy-d-erythro-pentitol.

The “naked sugar” (+)-(1R,2R,4R)-2-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((+)-3) was converted in ten synthetic steps into the new C-nucleoside (1R)-1-C-(6′-amino-7′H-purin-8′-yl)-1,4-anhydro-3-azido-2,3-dideoxy- D-erythro-pentitol ((+)-2) in 19% overall yield.     

Asymmetric cyclization of 2-alkenylphenols. A comparative study on the use of palladium(II) and titanium(IV) complexes

The oxidative cyclization of 2-(3-pentenyl)phenol catalyzed by [(η³-pinene)PdOAc]₂ gives optically active (+)-2-vinylchroman (25% e.e.), while (−)-2-(1-hydroxyethyl)chroman (56% e.e.) is formed as a single diastereomer upon treatment with t-BuOOH in the presence of Ti(OⁱPr)₄ and -(+)-diethyl tartrate. 2-(2-Butenyl)phenol also undergoes the Ti-promoted asymmetric cyclization to give (2S,1′R)-(−)-2-(1-hydroxyethyl)-2,3-dihydrobenzofuran (29% e.e.).     

(R)-bis-Binaphthoxy iodo lanthanides as catalysts for Diels–Alder reactions

[(R)-1,1′bi-2,2′-Naphthoxy]LnI(THF)₂ (Ln: Yb, Sm, La) 5 have been prepared by reaction of the bispotassium salt of (R)-binaphthol with lanthanide triiodides, and characterized. They are active catalysts for Diels–Alder reactions although with low asymmetric inductions. The lanthanum iodo bisbinaphthoxide gives a slightly higher enantiomeric excess than the two other complexes.     

Resolution of 1-substituted-3-methyl-3-phospholene 1-oxides by molecular complex formation with TADDOL derivatives

The antipodes of 1-aryl-, 1-alkyl- and 1-alkoxy-3-methyl-3-phospholene 1-oxides 1a–h and 1-phenyl-3-methyl-3-phospholene 1-sulfide 1i were separated in good yields and high enantiomeric excesses (up to >99% ee) by resolution via formation of diastereomeric complexes with either (−)-(4R,5R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane 2 (TADDOL) or (−)-(2R,3R)-,,′,′-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol 3. The stereostructure of the supramolecular formations and the absolute configurations of the 3-phospholene oxides 1a, 1e and 1f were elucidated by single crystal X-ray crystallography. CD spectroscopy was also useful in determining the absolute configurations of some phospholene oxides 1b, 1c, 1g and 1h.     

Tris-chelate complexes with chiral ligands: In search of diastereoisomeric selectivity with remote stereogenic centres

The chiral ligands, 4,4′-bis{(1S,2R,4S)-(−)-bornyloxy}-2,2′-bipyridine, (1S,2R,4S)-1, and 4,4′-bis{(1R,2S,4R)-(+)-bornyloxy}-2,2′-bipyridine, (1R,2S,4R)-1, have been prepared and characterized by spectroscopic techniques and, for (1S,2R,4S)-1, by single crystal X-ray diffraction. Despite the use of enantiomerically pure ligands, the formation of the complexes [Fe((1S,2R,4S)-1)₃]²⁺, [Ru((1S,2R,4S)-1)₃]²⁺, [Ru((1S,2R,4S)-1)(bpy)₂]²⁺ and [Ru((1R,2S,4R)-1)(bpy)₂]²⁺ proceeds without preference for either the Δ or Λ-diastereoisomers.     

3-exo,3′-exo-(1R,1′R)-Bithiocamphor — a versatile source for functionally different 3,3′-bibornane derivatives, II. 1 An access to 3-exo,3′-exo-(1r,1′r)-bicamphor and related compounds

3-exo,3′-exo-(1R,1′R)-bicamphor (12) is obtained from 3-exo,3′-exo-(1R,1′R)-bithtiocamphor (3) by condensation with hydrazine hydrate followed by hydrolysis of the resulting dihydropyridazine 11. Deprotonation of 12 with NaH and subsequent treatment with potassium hexacyanoferrate (III) furnishes the 2,2′-dioxo-3,3′-bibornanylidene 13, whilst reduction of 12 with L1AlH₄ affords the 3,3′-biisoborneol 16. Further related transformations to various 2,2′-difunctional 3,3′-bibornane derivatives are described, which are could be of interest as chiral ligands     

Syntheses and absolute configurations of the cytokinins 1′-methylzeatin and its 9-riboside

On the basis of the chiral syntheses of (1′R)-I and (1′S)-I and of their 9-ribosides (1″R)-III and (1″S)-III from D- and L-alanines, the structures of the cytokinins 1′-methylzeatin and its 9-riboside have been established to be (1′R)-I and (1″R)-III.     

New chiral P-ligands: P-amino- and P-cycloalkoxy dibenzo[c.e][1,2]oxaphosphorines

The reaction of racemic chloro-dibenzo[c.e][1,2]oxaphosphorine with (S)-(−)--methyl-benzylamine and (1R,2S,5R)-(−)-menthol led to a mixture of optically active diastereomers of the corresponding phosphonous derivatives. The isomers were separated in a diastereomeric excess of 71–93% at the phosphonic oxide and/or at the phosphonous borane stage. The P(III) boranes are suitable precursors of the P-ligands. The absolute P-configuration in one of the menthyl phosphonates isolated was determined by single crystal X-ray analysis.     

A new C2-symmetric chiral bisphosphine ligand containing a bioxazole backbone: highly enantioselective hydrosilylation of ketones

C₂-Symmetric (4S,4′S)-2,2′-bis(o-diphenylphosphinophenyl)-4,4′,5,5′-tetrahydro-4,4′-bi(1,3-oxazole) (1, Phos-Biox) has been designed and synthesized as a chiral ligand for metal-catalyzed reactions. The Phos-Biox 1 was found to be an efficient ligand for rhodium(I)-catalyzed asymmetric reduction of prochiral acetophenones with diphenylsilane to give optically active secondary alcohols of up to 97% ee.     

Synthesis of a novel cage-functionalized chiral binaphthol host: a potential new agent for enantioselective recognition of chiral ammonium salts

Optically active, cage-functionalized crown ether (R)-3 which contains a 1,1′-bi-2-naphthol moiety has been prepared. Subsequently, the ability of (R)-3 to selectively recognize the enantiomers of guest ammonium salts, i.e., 4 and 5 in transport experiments was studied. Host (R)-3 displays significantly enhanced enantiomeric selectivity toward complex formation with 4 vis-à-vis complex formation with 5. The relative energetics of various relevant host–guest complexes have been investigated computationally.     

Highly stereoselective reduction of methyl ketone complexes of the chiral Lewis acid [(η-C5H5)Re(NO)(PPh3)] by K(s-C4H9)3BH; synthesis of optically active secondary alcohols and derivatives

Reaction of optically active ketone complexes (+)-(R)-[(η⁵-C₅H₅)Re(NO)-(PPh₃)(η¹-O=C(R)(CH₃)]⁺ BF₄⁻ (R = CH₂CH₃, CH(CH₃)₂m C(CH₃)₃, C₆H₅) with K(s-C₄H₉)₃BH gives alkoxide complexes (+)-(RS)-(η⁵-C₅H₅)Re(NO)(PPh₃)-(OCH(R)CH₃) (73–90%) in 80–98% de. The alkoxide ligand is then converted to Mosher esters (93–99%) of 79–98% de.     

Synthesis of new chiral amino ether derivatives: synthetic application of meso aziridinium ions prepared from β-amino alcohols

Methods of synthesis of new chiral amino ether derivatives through the opening of aziridinium ions, prepared in situ using trans-(±)-2-(1-N,N-dialkylamino)cyclohexyl mesylate with (R)-(+)-1,1′-bi-2-naphthol, are described. The (R,R,R)-diastereomer was obtained as the major product and isolated as an enantiopure salt, and characterized by single crystal X-ray analysis. The C₂-chiral (R,R,R,R,R)-diamino ether was obtained as the major product by opening of the aziridinium ion, prepared using trans-(±)-2-(1-pyrrolidino)cyclohexyl mesylate and (R)-(+)-1,1′-bi-2-naphthol in the presence of aq NaOH. This was also characterized by single crystal X-ray analysis.     

Studies on the synthesis of biphenylneolignans. Part 1: Enantioselective synthesis of (S,S)- and (R,R)-2,2′-dimethoxy-4-(3-hydroxy-1-propenyl)-4′-(1,2,3-trihydroxypropyl)diphenyl ether

Two erythro-isomers of 2,2′-dimethoxy-4-(3-hydroxy-1-propenyl)-4′-(1,2,3-trihydroxypropyl)diphenyl ether, (7′S, 8′S)-9 and (7′R, 8′R)-9, were synthesized in seven steps, in which an improved method for the synthesis of the key intermediate 3 was developed. The absolute configuration of the target molecules was also confirmed.     

Synthesis of (+)-carpamic acid from (+)-alanine

(+)-Carpamic acid [(2′R,5′S,6′S)-8-(5′-hydroxy-6′-methylpiperidin-2′-yl)octanoic acid, 1] was synthesized from (S)-alanine, employing intramolecular and reductive amination of acyclic amino ketone 8 as the key step to generate the piperidine ring.     

(R)-Binaphthoxy diiodide lanthanides

The synthesis and characterization of novel enantiopure binaphthoxy-diiodo lanthanides [(R)-2-(1-naphthol)-1′-naphthoxide)LnI₂(THF)₃] (Ln=Sm (4a), Yb (4b), La (4c)) are described. These complexes have been prepared by reacting the mono potassium salt of (R)-binaphthol with the corresponding lanthanide triiodides and were characterized by elemental analysis, IR and NMR spectroscopies. Recrystallization of 4c from THF–hexane led to monocrystals of [(R)-2-(1-naphthol)-1′-naphthoxide)]-diiodolanthane-tetrakistetrahydrofurane] (4c*). Complex 4c* crystallizes in the orthorhombic space group, P2₁2₁2₁ with cell parameters a=13.086(1) Å, b=15.496(1) Å, c=18.854(1) Å, V=3823.2(6) ų, and Z=4.     

Oligomeric flavanoids. Part 13. Synthesis of profisetinidins based on (−) robinetinidol and (+) -epifisetinidol

Acid-catalyzed condensation of (+)-mollisacacidin-[(2R, 3S, 4R)-2, 3-trans-3, 4-trans-flavan-3,3′,4,4′,7-pentaol] with an excess of (−)-robinetinidol[(2R,3S)-2,3-trans-flavan-3,3′,4′,5′,7-pentaol] afforded a novel series of bi-, tri-, and tetraflavanoid profisetinidins. They are accompanied by (−)-fisetinidol-(4,2′)-(−)-robinetinidol which results from the pyrogallol B-ring of (−)-robinetinidol serving as nucleophile competing with its resorcinol A-ring in coupling with a C-4 carbocationic intermediate. Similar condensation with (+)-epifisetinidol[(2S,3S)-2,3-cis-flavan-3,3′,4′,7-tetraol] led to the exclusive formation of [4,6]-interflavanyl bonds, these units being ‘linearly’ arranged in the tetraflavanoid analogue in contrast to the ‘branched’ nature of the (−)-robinetinidol homologue.     

Conformational and structural analysis of N-N′-bis(4-methoxybenzylidene)ethylenediamine

The Schiff base compound, N-N′-bis(4-methoxybenzylidene)ethylenediamine (C₁₈H₂₀N₂O₂) has been synthesized and its crystal structure has been investigated by X-ray analysis and PM3 method. The compound crystallizes in monoclinic space group P2₁/n with a=10.190(1), b=7.954(1), c=10.636(1) Å, β=111.68(1)°, V=801.1(1) ų, Z=2 and D_cal=1.229 Mgm⁻³. The title structure was solved by direct methods and refined to R=0.056 for 2414 reflections [I>3.0σ(I)] by full-matrix anisotropic least-squares methods. The energy profile of the compound was calculated by PM3 method as a function of θ[N1′–C9′–C9–N1]. The most stable molecular structure of the title compound is the anti conformation, which is different in energy by 5.0 and 1.0 kcal mol⁻¹ from the eclipsed conformation I and gauche conformations, (III and V), respectively.     

Facile synthesis of enantiopure 1,1′-binaphthyl-2,2′-dicarboxylic acid via lipase-catalyzed kinetic resolution

Enantiopure 1,1′-binaphthyl-2,2′-dicarboxylic acids (R)-1 and (S)-1 have been synthesized through the lipase-catalyzed kinetic resolution of the racemic 2,2-bis(hydroxymethyl)-1,1′-binaphthyl (±)-2 and subsequent oxidation of the hydroxymethyl groups.