Total synthesis of apoptolidin: completion of the synthesis and analogue synthesis and evaluation

The total synthesis of apoptolidin (1) is reported together with the design, synthesis, and biological evaluation of a number of analogues. The assembly of key fragments 6 and 7 to vinyl iodide 3 via dithiane coupling technology was supplemented by a second generation route to this advanced intermediate involving a Horner-Wadsworth-Emmons coupling of fragments 22 and 25. The final stages of the synthesis featured a Stille coupling between vinyl iodide 3 and vinylstannane 2, a Yamaguchi lactonization, a number of glycosidations, and final deprotection. The developed synthetic technology was applied to the construction of several analogues including 74, 75, and 77 which exhibit significant bioactivity against tumor cells.     

Heterodiene synthesis

Both 1,4,-cycloaddition with the formation of a 1,4-dihydro-1,2,4-triazene derivative and electrophilic addition of acetyldicarboxylic acid ester to the secondary nitrogen atom occur during the reaction of acetylenedicarboxylic acid ester with 1,5-diphenyl-3-methyl-3-methylformazan. In the case of l,5.diphenylformazan, the reaction proceeds only in the second direction.See [3] for Communication II.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1704–1705, December, 1970.     

Tin-mediated synthesis of lyso-phospholipids

1-O-Acyl-sn-glycero-3-phosphocholine and 1-O-acyl-sn-glycero-3-phosphoric acid have been prepared selectively and with high yields from the corresponding diols, glycerophosphoryl choline and glycerol-3-phosphate. Starting from the diols, the activated tin ketals were prepared in 2-propanol by reaction with dialkyltin oxide. The intermediates were acylated in the same solvent with long-chain fatty acid chlorides, giving the corresponding 1-acyl-lyso-phospholipids in high yield and with complete regioselectivity. The catalytic nature of the tin-mediated acylation and the relevance of the solvent are discussed.     

Total synthesis of (+)-pederin. 2. Stereocontrolled synthesis of (+)-benzoylselenopederic acid and total synthesis of (+)-pederin

(+)-Benzoylselenopederic acid (1), a left half of (+)-pederin (3), was synthesized stereoselectively based on the Zn(BH₄)₂ reduction and total synthesis of (+)-pederin (3) was accomplished from 1 and the previously synthesized 2.     

The synthesis of zinniol

Zinniol 10, 3 - methoxy - 4 -methyl - 5 (3 - methyl - 2 - butenyloxy) - 1,2 - benzenedimethanol, a metabolite isolated from the pathogenic fungus Alternaria zinniae, has been synthesised.     

The synthesis of dinaphthothiophenes

The synthesis of dinaphtho[1,2-b:2′,3′-d]thiophene ( 6 ), dinaphtho[2,1-b:2′,3′-d]thiophene ( 15 ), dinaphtho-[1,2-b:1′,2′-d]thiophene ( 20 ), dinaphtho[2,1-b:1′,2′-d]thiophene ( 26 ), dinaphtho[2,3-b:2′,3′-d]thiophene ( 37 ) and dinaphtho[1,2-b:2′,1′-d]thiophene ( 45 ) has been accomplished.     

The synthesis of berberastine

The structure of berberastine iodide (1a) has been confirmed by a synthesis of its racemate. The key intermediate is the 7,8-dimethoxy-3-arylisoquinoline derivative (3a) and several methods for its formation were studied.     

The synthesis of thienocycloheptenoindoles

A synthesis of the methylthieno[3,2-c]cyclohepteno[b]indole 7 from 2-methylthieno[3,2-b]cycloheptanone 3 is described. Unsuccessful attempts to prepare the isomeric thienocycloheptenoindole system present in formula 2 , from the dihydrobenzothiophenone 8 , and from derivatives of 5-(2-thienyl)-4-oxopentanoic acid, 17 and 18 , and from N-benzylcycloheptindol-1-one 22 were unsuccessful. The preparation of 4,5-dihydro-2-phenyl-1-thienylmethyl-3H-pyridazin-3-one 20 and of the 5-aminopyrazole 21 are reported.     

Size-controlled synthesis of magnetite nanoparticles

Monodisperse magnetite nanoparticles have been synthesized by high-temperature solution-phase reaction of Fe(acac)3 in phenyl ether with alcohol, oleic acid, and oleylamine. Seed-mediated growth is used to control Fe3O4 nanoparticle size, and variously sized nanoparticles from 3 to 20 nm have been produced. The as-synthesized Fe3O4 nanoparticles have inverse spinel structure, and their assemblies can be transformed into gamma-Fe2O3 or alpha-Fe nanoparticle assemblies, depending on the annealing conditions. The reported procedure can be used as a general approach to various ferrite nanoparticles and nanoparticle superlattices.     

Hydrolysis-free synthesis of 3-aminocoumarins

A commonly encountered problem in the synthesis of 3-aminocoumarins is the formation of 3-hydroxycoumarins. A solution to this problem, which involves non-aqueous formation of the 3-aminocoumarin system, is described.     

Template synthesis of 1,4,7-triphosphacyclononanes

Iron(II) templates based on a [(eta(5)-Cp(R))Fe]+ core have been employed for the successful synthesis of 1,4,7-triphosphacyclononane derivatives (9-aneP3R'3) from a range of appropriately functionalized coordinated diphosphines and monophosphines. 1,2-Diphosphinoethane (1,2-dpe) or (2-phosphinoethyl)phenylphosphine (Phdpe) undergo a base-catalyzed Michael-type addition to trivinylphosphine, divinyl(benzyl)phosphine, or divinyl(phenyl)phosphine in [(eta(5)-Cp(R))Fe(diphosphine)(monophosphine)]+ complexes (2a-j) to give [(eta(5)-Cp(R))Fe(9aneP3R'3)]+ derivatives (4a-j) containing coordinated triphosphacyclononanes bearing one (with Phdpe) or two (with 1,2-dpe) secondary phosphine donors. The rates of macrocyclization show a dependence on the nature of the substituent(s) R on the cyclopentadienyl ligand with increased rates being observed along the series R = H5 < (Me3Si)H4 < 1,3-(Me3Si)2H3 approximately = Me5. For coupling reactions with trivinylphosphine, a pendant vinyl function remains in the macrocyclic product (4a-g) which is readily hydrogenated to the corresponding ethyl derivatives (5a-g). Further functionalization of coordinated secondary phosphines in the initially formed macrocycles (5a-g) is achieved by proton abstraction followed by addition of the appropriate alkyl halide electrophile and gives rise to tritertiary-triphospha-cyclononanes (7a-g, 7l, 7m). All new complexes have been fully characterized by spectroscopic and analytical methods in addition to the structural determination by single-crystal X-ray techniques of [{eta(5)-(Me3Si)2C5H3)Fe(9-aneP3H2C2H3)]PF6, 4c, and [(eta(5)-Me3SiC5H4)Fe(9-aneP3Et3)]BF4, 7b. 1,4,7-Triethyl-1,4,7-triphosphacyclononane is released from its metal template (7a, 7b) by treatment with either H2O2 or Br2/H2O to give the trioxide 9-aneP3(O)3Et3 (8). Attempts to recover the trivalent phosphorus species, 1,4,7-triethyl-1,4,7-triphosphacyclononane, from the trioxide by reduction proved unsuccessful.     

Catalytic synthesis of 1,3-propylenediamines

The hydrogenation on Raney nickel of 3-alkenyl-substituted pyrazolines and also of 3-methyl-5-(2-furyl)-1H-pyrazoline and 3,3′-bipyrazoline afforded substituted 1,3-diaminobutanes, 1,3-diaminopentanes, 1,3-diaminohexane, and 1,3,4,6-tetraaminohexane. Under the same conditions from 3-acetyl-4-(2-furyl)-1H-pyrazoline 3-amino-2-methyl-4-(2-furyl)pyrrolidine was obtained.     

Convenient, rapid synthesis of rare earth orthochromites LnCrO by self-propagating high-temperature synthesis

Lanthanide orthochromites of general formula LnCrO₃ (Ln=La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Tb, Lu) and YCrO₃ have been made by self-propagating high-temperature synthesis (SHS). Four different SHS reactions were found to form LnCrO₃: reaction of Ln₂O₃, Cr and CrO₃ with NaClO₄ or Ba (ClO₄)₂ in air; reaction of Ln₂O₃, Cr and CrO₃ in oxygen; reaction of LnCl₃, CrCl₃ and NaO₂ or Na₂O₂ in air and reaction of Ln (NO₃)₃, Cr and melamine in air. Reactions were studied by DTA and TGA experiments which showed exotherms and weight losses associated with the initiation temperatures (ca. 350°C) of the SHS reactions. Maximum reaction temperature T_c and propagation velocity U_c were measured for selected reactions. X-ray powder diffraction showed a single phase orthorhombic perovskite structure was produced in all reactions. Systematic changes in the lattice parameters, cell volume and pycnometrical densities were seen as a function of lanthanide atomic number. SHS prepared LnCrO₃ samples were all shown to be weak antiferromagnets. IR spectra for the LnCrO₃ materials showed bands at 635, 480, 440, 350 and 180 cm⁻¹.     

A new synthesis of phthalimidines

A new synthesis of phthalimidines is described. 3-Acyloxy-2-aryl- and 2-acylamino-3-acyloxyphthalimidines were prepared by the reaction of 3-arylaminophthalides or o-formylbenzoic acid acylhydrazones with acetic or propionic anhydrides. Their reactions with O-, N-, S-, and C-nucleophiles were studied. The structure of 2-acetyl(cyanoacetyl)amino-3-acetoxyindolin-1-one was confirmed by X-ray diffraction analysis.     

Asymmetric synthesis of triepoxyzerumbol

The achiral sesquiterpene zerumbone 1, which is readily available from wild ginger, has a unique functionality and reactivity making it a convenient starting material for its conversion into useful compounds, such as paclitaxel. Optically active triepoxyzerumbol (−)-3 and its acetate (+)-4 were synthesized by lipase-catalyzed enantioselective transesterification of racemic 3. Under optimized conditions, a lipase from Alcaligenes sp. (Meito QL) catalyzed the reaction of racemic 3 with isopropenyl acetate in THF at 35 °C to afford (1S)-3 and (1R)-4 with an E-value of 79. The absolute configuration of (1R)-4 was determined by single crystal X-ray diffraction of its ester with a chlorine atom using the anomalous dispersion effect.     

Alternative synthesis of alverine

An efficient synthesis of alverine via iron-catalyzed double cross-coupling of (2E)-3-chloro-N-[(2E)-3-chloroprop-2-en-1-yl]-N-ethylprop-2-en-1-amine with phenylmagnesium bromide is described.     

The synthesis and structure of triphenylsiloxycyclotriphosphazenes

The triphenylsiloxy-substituted cyclotriphosphazenes, N₃P₃Cl₅OSiPh₃, gem-N₃P₃Cl₄(OSiPh₃)₂, N₃P₃(OSiPh₃)₆, and N₃P₃(OPh)₅OSiPh₃, have been prepared. The synthesis of gem-N₃P₃Cl₄(OSiPh₃)₂ involves the reaction of (NPCl₂)₃ with Ph₃SiONa to form the intermediates gem-N₃P₃Cl₄(OSiPh₃)₂(ONa) and gem-N₃P₃Cl₄(ONa)₂, which yield gem-N₃P₃Cl₄(OSiPh₃)₂ when treated with Ph₃SiCl. The compounds N₃P₃Cl₅OSiPh₃ and N₃P₃(OSiPh₃)₀ are formed by the condensation reactions of N₃P₃Cl₅OBuⁿ and N₃P₃(OBuⁿ)₆, respectively, with Ph₃SiCl. The compound N₃P₃(OPh)₅OSiPh₃ is synthesized by the reaction between N₃P₃(OPh)₅Cl and Et₃SiONa to first give the intermediate N₃P₃(OPh)₅ONa, which yields N₃P₃(OPh)₅OSiPh₃ when reacted with Ph₃SiCl. The structural characterization and properties of these compounds are discussed. The crystal and molecular structure of gem-N₃P₃Cl₄(OSiPh₃)₂ has been investigated by single-crystal X-ray diffraction techniques. The crystals are monoclinic with the space group P2₁/c with a = 16.850(8), b = 12.829(4), c = 18.505(15) Å, and β = 101.00(6)° with V = 3927 ų and Z = 4. © 1996 John Wiley & Sons, Inc.     

Total synthesis of amphidinolide E

A convergent and highly stereocontrolled synthesis of amphidinolide E (1) has been accomplished. The synthesis features a highly diastereoselective (>20:1) BF3.Et2O promoted [3+2] annulation reaction between aldehyde 3 and allylsilane 4 to afford substituted tetrahydrofuran 2.     

A stereospecific synthesis of oxazolinyloxiranes

Lithiooxiranes 3a and 3b, generated by deprotonation of oxiranes 2a and 2b with s-BuLi at -100 degrees C in Et(2)O, were found to be chemically very stable. trans-Lithiooxirane 3a was also configurationally stable and reacted stereospecifically with electrophiles to give 4a--k. In contrast, cis-lithiooxirane 3b was found to be configurationally much less stable and reacted with electrophiles affording mixtures of diastereomers 4, 7, and 8. After only a very short reaction time, 3b too reacted with electrophiles highly stereospecifically. Deprotonation--deuteration and deprotonation--alkylation of chiral oxazolinyloxiranes 12a and 12b to give oxiranes 12c and 12d were also examined. Semiempirical and ab initio calculations were carried out in an effort to explain the observed stereochemistry.     

Total synthesis of formamicin

The enantioselective total synthesis of the cytotoxic plecomacrolide natural product formamicin (1) is described. Key aspects of this synthesis include the efficient transacetalation reactions of MOM ethers 28 and 38 to form the seven-membered formyl acetals 29 and 39, a late-stage Suzuki cross-coupling reaction of the highly functionalized vinyl boronic acid 6 and vinyl iodide 7, a highly beta-selective glycosidation reaction of beta-hydroxy ketone 4 with 2,6-dideoxy-2-iodoglucopyranosyl fluoride 3, and the global desilylation of penultimate intermediate 77 mediated by in situ generated Et(3)N.2HF.