Solid‐phase Total Synthesis of (−)‐Apratoxin A and Its Analogues and Their Biological Evaluation

Two approaches for the solid‐phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer‐support, macrolactamization of 10 , followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid‐phase peptide synthesis by using amino acids 13 – 15 and 18 . The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxin A, and O‐methyl tyrosine can be replaced by 7‐azidoheptyl tyrosine without loss of activity. The 1,3‐dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.     

Supramolecular structures of bis‐thionooxalamic acid esters derived from (±)‐cyclohexane‐1,2‐diamine and (±)‐1,2‐diphenylethylenediamine

The bis‐thionooxalamic acid esters trans‐(±)‐diethyl N,N′‐(cyclohexane‐1,2‐diyl)bis(2‐thiooxamate), C₁₄H₂₂N₂O₄S₂, and (±)‐N,N′‐diethyl (1,2‐diphenylethane‐1,2‐diyl)bis(2‐thiooxamate), C₂₂H₂₄N₂O₄S₂, both consist of conformationally flexible molecules which adopt similar conformations with approximate C₂ rotational symmetry. The thioamide and ester parts of the thiooxamate group are significantly twisted along the central C—C bond, with the S=C—C=O torsion angles in the range 30.94 (19)–44.77 (19)°. The twisted s‐cis conformation of the thionooxamide groups facilitates assembly of molecules into a one‐dimensional polymeric structure via intermolecular three‐center C=S...NH...O=C hydrogen bonds and C—H...O interactions formed between molecules of the opposite chirality.     

Rietveld refinement of the cocrystal 2,4‐dihydroxybenzoic acid–N′‐(propan‐2‐ylidene)nicotinohydrazide (1/1)

A further example of using a covalent‐bond‐forming reaction to alter supramolecular assembly by modification of hydrogen‐bonding possibilities is presented. This concept was introduced by Lemmerer, Bernstein & Kahlenberg [CrystEngComm (2011), 13 , 55–59]. The title structure, C₉H₁₁N₃O·C₇H₆O₄, which consists of a reacted niazid molecule, viz.N′‐(propan‐2‐ylidene)nicotinohydrazide, and 2,4‐dihydroxybenzoic acid, was solved from powder diffraction data using simulated annealing. The results further demonstrate the relevance and utility of powder diffraction as an analytical tool in the study of cocrystals and their hydrogen‐bond interactions.     

10‐Step Asymmetric Total Synthesis and Stereochemical Elucidation of (+)‐Dragmacidin D

The asymmetric synthesis of dragmacidin D ( 1 ) was completed in 10 steps. Its sole stereocenter was set by using direct asymmetric alkylation enabled by a C₂‐symmetric tetramine and lithium N‐(trimethylsilyl)‐tert‐butylamide as the enolization reagent. A central Larock indole synthesis was employed in a convergent assembly of the heterocyclic subunits. The stereochemical evidence from this work strongly supports the predicted S configuration at the 6′′′ position, which is consistent with other members of the dragmacidin family of natural products.     

Conformation and tautomerism of methoxy‐substituted 4‐phenyl‐4‐thiazoline‐2‐thiones: a combined crystallographic and ab initio investigation

4‐Phenyl‐4‐thiazoline‐2‐thiol is an active pharmaceutical compound, one of whose activities is as a human indolenamine dioxygenase inhibitor. It has been shown recently that in both the solid state and the gas phase, the thiazolinethione tautomer should be preferred. As part of both research on this lead compound and a medicinal chemistry program, a series of substituted arylthiazolinethiones have been synthesized. The molecular conformations and tautomerism of 4‐(2‐methoxyphenyl)‐4‐thiazoline‐2‐thione and 4‐(4‐methoxyphenyl)‐4‐thiazoline‐2‐thione, both C₁₀H₉NOS₂, are reported and compared with the geometry deduced from ab initio calculations [PBE/6‐311G(d,p)]. Both the crystal structure analyses and the calculations establish the thione tautomer for the two substituted arylthiazolinethiones. In the crystal structure of the 2‐methoxyphenyl regioisomer, the thiazolinethione unit was disordered over two conformations. Both isomers exhibit similar hydrogen‐bond patterns [R₂²(8) motif] and form dimers. The crystal packing is further reinforced by short S…S interactions in the 2‐methoxyphenyl isomer. The conformations of the two regioisomers correspond to stable geometries calculated from an ab initio energy‐relaxed scan.     

One‐step synthesis of 6‐acetamido‐3‐(N‐(2‐(dimethylamino) ethyl) sulfamoyl) naphthalene‐1‐yl 7‐acetamido‐4‐hydroxynaphthalene‐2‐sulfonate and its characterization with 1D and 2D NMR techniques

A one‐step method was reported for the synthesis of 6‐acetamido‐3‐(N‐(2‐(dimethylamino) ethyl) sulfamoyl) naphthalene‐1‐yl 7‐acetamido‐4‐hydroxynaphthalene‐2‐sulfonate by treating 7‐acetamido‐4‐hydroxy‐2‐naphthalenesulfonyl chloride with equal moles of N, N‐dimethylethylenediamine in acetonitrile in the presence of K₂CO₃. The chemical structure of the obtained compounds was characterized by MS, FTIR, ¹H NMR, ¹³C NMR, gCOSY, TOCSY, gHSQC, and gHMBC. The chemical shift differences of ¹H and ¹³C being δ 0.04 and 0.2, respectively, were unambiguously differentiated. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis of (1α)‐1,25‐Dihydroxyvitamin D3 with a β‐Positioned Seven‐Carbon Side Chain at C(12)

A convergent synthesis of an analogue of (1α)‐1,25‐dihydroxyvitamin D₃ ( 1b ) with a C₇ side chain at C(12), i.e., of 5 (Fig.), is described. A key step of the synthesis is the assembly of the triene system by a Pd^II‐catalyzed ring closure of an enol triflate (‘bottom’ fragment) followed by coupling of the resulting Pd^II intermediate with an alkenylboronate (‘upper’ fragment) (Scheme 2). The synthetic strategy allows isotopic labelling at the end of the synthesis.     

A novel 18‐membered metallocycle in {2,5‐bis[3‐(1H‐1,3‐imidazol‐1‐ylmethyl)phenyl]‐1,3,4‐oxadiazole}dichloridocobalt(II)

The title molecular complex, [CoCl₂(C₂₂H₁₈N₆O)], features a novel 18‐membered Co‐containing metallocycle. The Co^II atom lies in a fairly regular tetrahedral geometry defined by two imidazole N‐atom donors from one 2,5‐bis[3‐(1H‐1,3‐imidazol‐1‐ylmethyl)phenyl]‐1,3,4‐oxadiazole (L) ligand and two chloride anions. The coordinating orientation of the L ligand plays an important role in constructing the metallocycle complex. The complexes form a three‐dimensional supramolecular assembly via nonclassical C—H...Cl and C—H...N hydrogen bonds and π–π interactions.     

Hydrogen‐bonded networks in trans‐3‐(3‐pyridyl)acrylic acid and rctt‐3,3′‐(3,4‐dicarboxycyclobutane‐1,2‐diyl)dipyridinium dichloride

The structure of trans‐3‐(3‐pyridyl)acrylic acid, C₈H₇NO₂, (I), possesses a two‐dimensional hydrogen‐bonded array of supramolecular ribbons assembled via heterodimeric synthons between the pyridine and carboxyl groups. This compound is photoreactive in the solid state as a result of close contacts between the double bonds of neighbouring molecules [3.821 (1) Å] along the a axis. The crystal structure of the photoproduct, rctt‐3,3′‐(3,4‐dicarboxycyclobutane‐1,2‐diyl)dipyridinium dichloride, C₁₆H₁₆N₂O₄²⁺·2Cl⁻, (II), consists of a three‐dimensional hydrogen‐bonded network built from crosslinking of helical chains integrated by self‐assembly of dipyridinium cations and Cl⁻ anions via different O—H...Cl, C—H...Cl and N⁺—H...Cl hydrogen‐bond interactions.     

Synthesis and properties of soluble and light‐colored poly(amide‐imide‐imide)s on the basis of tetraimide‐dicarboxylic acid condensed from 4,4′‐oxydiphthalic anhydride, 2,2‐bis[4‐(4‐aminophenoxy)phenyl]propane,and m‐aminobenzoic acid,and various aromatic diamines

A new type of tetraimide‐dicarboxylic acid ( I ) was synthesized starting from the ring‐opening addition of m‐aminobenzoic acid, 4,4′‐oxydiphthalic anhydride, and 2,2‐bis[4‐(4‐aminophenoxy)phenyl]propane at a 2:2:1 molar ratio in N‐methyl‐2‐pyrrolidone (NMP), followed by cyclodehydration to the diacid I . A series of soluble and light‐colored poly(amide‐imide‐imide)s ( III _a–j) was prepared by triphenyl phosphite‐activated polycondensation from I with various aromatic diamines ( II _a–j). All films cast from N,N‐dimethylacetamide (DMAc) had cutoff wavelengths shorter than 390 nm (374–390 nm) and b* values between 25.26 and 43.61; these polymers were much lighter in color than the alternating trimellitimide series. All of the polymers were readily soluble in a variety of organic solvents such as NMP, DMAc, N,N‐dimethylformamide, dimethyl sulfoxide, and even in less polar m‐cresol and pyridine. Polymers III _a–j afforded tough, transparent, and flexible films that had tensile strengths ranging from 96 to 118 MPa, elongations at break from 9 to 11%, and initial moduli from 2.0 to 2.5 GPa. The glass‐transition temperatures of the polymers were recorded at 240–268 °C. They had 10% weight loss at a temperature above 540 °C and left more than 55% residue even at 800 °C in nitrogen. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 707–718, 2002; DOI 10.1002/pola.10153     

Novel thermoresponsive fluorinated double‐hydrophilic poly{[N‐(2,2‐difluoroethyl)acrylamide]‐b‐[N‐(2‐fluoroethyl)acrylamide]} block copolymers

Novel thermoresponsive double‐hydrophilic fluorinated block copolymers were successfully synthesized by reversible addition‐fragmentation chain transfer (RAFT) polymerization. Poly[N‐(2,2‐difluoroethyl)acrylamide] (P2F) was synthesized via RAFT polymerization of N‐(2,2‐difluoroethyl)acrylamide (M2F) using 2‐dodecylsulfanylthiocarbonylsulfanyl‐2‐methylpropionic acid (DMP) as the chain transfer agent (CTA) and 2,2′‐azobisisobutyronitrile (AIBN) as the initiator. The resulting P2F macroCTA was further chain extended with N‐(2‐fluoroethyl)acrylamide (M1F) to yield poly{[N‐(2,2‐difluoroethyl)acrylamide]‐b‐[N‐(2‐fluoroethyl)acrylamide]} (P2F‐b‐P1F) block copolymers with different lengths of the P1F block. Molecular weight and molecular weight distribution were determined by gel permeation chromatography. The average molecular weight (M_n) of the resulting polymers ranged from 2.9 × 10⁴ to 5.8 × 10⁴ depending on the length of the P1F block. The molecular weight distribution was low (M_w/M_n = 1.11–1.19). Turbidimetry by UV‐Visble (UV‐Vis) spectroscopy, dynamic light scattering, and in situ temperature‐dependent ¹H NMR measurements demonstrated that the P2F block underwent a thermal transition from hydrophilic to hydrophobic, which in turn induced self‐assembly from unimers to aggregates. Transmission electron microscopy studies demonstrated that polymeric aggregates formed from an aqueous solution of P2F‐b‐P1F at 60 °C were disrupted by cooling down to 20 °C and regenerated by heating to 60 °C. Temperature‐triggered release of a model hydrophobic drug, coumarin 102, was also demonstrated. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Kinetics and mechanism for the formation of o‐carboxy(N‐methyl)‐benzohydroxamic acid in the cleavage of ethyl N‐[o‐(N‐methyl‐N‐hydroxycarbamoyl)‐benzoyl]carbamate in N‐methylhydroxylamine,acetate, and phosphate buffers

The rate of cleavage of ethyl N‐[o‐(N‐methyl‐N‐hydroxycarbamoyl)benzoyl]‐ carbamate (ENMBC) in the buffer solutions containing N‐methylhydroxylamine, acetate + N‐methylhydroxylamine, and phosphate + N‐methylhydroxylamine followed an irreversible consecutive reaction path: ENMBC where A and B represent N‐hydroxyl group cyclized product of ENMBC and o‐(N‐methyl‐N‐hydroxycarbamoyl)benzoic acid, respectively. Both rate constants k_{1 obs} and k_{2 obs} showed the presence of buffer catalysis, but buffer catalysis turned out to be weak in the presence N‐methylhydroxylamine buffer, while it was strong in the presence of acetate and phosphate ones. Buffer‐independent rate constants k₁₀ and k₂₀ increased linearly with the increase in a_OH with definite intercepts. The values of molar absorption coefficient of A , obtained under varying total buffer concentrations at a constant pH, showed the presence of a fast equilibrium: A + CH₃NHOH ? C , where C represents N‐[o‐(N‐methyl‐N‐hydroxycarbamoyl)methyl]benzohydroxamic acid. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 427–437, 2003     

1‐Picolinyl‐5‐azido Thiosialosides: Versatile Donors for the Stereoselective Construction of Sialyl Linkages

With the picolinyl (Pic) group as a C‐1 located directing group and N₃ as versatile precursor for C5‐NH₂, a novel 1‐Pic‐5‐N₃ thiosialyl donor was designed and synthesized, based on which a new sialylation protocol was established. In comparison to conventional sialylation methods, the new protocol exhibited obvious advantages, including excellent α‐stereoselectivity in the absence of a solvent effect, broad substrate scope encompassing the challenging sialyl 8‐ and 9‐hydroxy groups of sialic acid acceptors, flexibility in sialoside derivative synthesis, high temperature tolerance and easy scalability. In particular, the applicability to the synthesis of complex and bioactive N‐glycan antennae when combined with the MPEP glycosylation protocol via the “latent‐active” strategy has been shown. Mechanistically, the excellent α‐stereoselectivity of the novel sialylation protocol could be attributed to the dramatic electron‐withdrawing effect of the protonated Pic groups, which was supported by control reactions and DFT calculations.     

4,6‐Dinitro‐N,N′‐di‐n‐octylbenzene‐1,3‐diamine, 4,6‐dinitro‐N,N′‐di‐n‐undecylbenzene‐1,3‐diamine and N,N′‐bis(2,4‐dinitrophenyl)octane‐1,8‐diamine

4,6‐Dinitro‐N,N′‐di‐n‐octylbenzene‐1,3‐diamine, C₂₂H₃₈N₄O₄, (I), 4,6‐dinitro‐N,N′‐di‐n‐undecylbenzene‐1,3‐diamine, C₂₈H₅₀N₄O₄, (II), and N,N′‐bis(2,4‐dinitrophenyl)octane‐1,8‐diamine, C₂₀H₂₄N₆O₈, (III), are the first synthetic meta‐dinitroarenes functionalized with long‐chain aliphatic amine groups to be structurally characterized. The intra‐ and intermolecular interactions in these model compounds provide information that can be used to help understand the physical properties of corresponding polymers with similar functionalities. Compounds (I) and (II) possess near‐mirror symmetry, with the octyl and undecyl chains adopting fully extended anti conformations in the same direction with respect to the ring. Compound (III) rests on a center of inversion that occupies the mid‐point of the central C—C bond of the octyl chain. The middle six C atoms of the chain form an anti arrangement, while the remaining two C atoms take hard turns almost perpendicular to the rest of the chain. All three molecules display intramolecular N—H...O hydrogen bonds between the amine and nitro groups, with the same NH group forming a bifurcated intermolecular hydrogen bond to the nitro O atom of an adjacent molecule. In each case, these interactions link the molecules into one‐dimensional molecular chains. In (I) and (II), these chains pack so that the pendant alkyl groups are interleaved parallel to one another, maximizing nonbonded C—H contacts. In (III), the alkyl groups are more isolated within the molecular chains and the primary nonbonded contacts between the chains appear to involve the nitro groups not involved in the hydrogen bonding.     

4,4′‐Bipyridyl N,N′‐dioxide–3‐hydroxy‐2‐naphthoic acid (1/2)

4,4′‐Bipyridyl N,N′‐dioxide crystallizes with 3‐hydr­oxy‐2‐naphthoic acid to give a centrosymmetric three‐component adduct, C₁₀H₈N₂O₂·2C₁₁H₈O₃, which is engineered into a two‐dimensional layer structure by two kinds of π–π inter­actions. Weak C—H⋯O inter­actions further link the two‐dimensional structure into a three‐dimensional structure.     

Pseudopoly(amino acid)s: Copolymerization of trans‐4‐hydroxy‐L‐proline and α‐hydroxy acids

A series of novel copolymers of trans‐4‐hydroxy‐L ‐proline (Hpr) and α‐ hydroxy acids [D,L ‐mandelic acid (DLMA) and D,L ‐lactic acid (DLLA)] were synthesized via direct melt copolymerization with stannous octoate as a catalyst. These new copolymers had pendant amine functional groups along the polymer backbone chain. The optimal reaction conditions for the synthesis of the copolymers were obtained with 4 wt % stannous octoate at 140 °C under vacuum for 16 h. The synthesized copolymers were characterized by IR spectrophotometry, proton nuclear magnetic resonance, differential scanning calorimetry, and Ubbelohde viscometry. The effects of the kinds of comonomers and the comonomer molar ratio on the polycondensation and glass‐transition temperature (T_g) were investigated. The T_g's of the copolymers shifted to lower temperatures with an increasing comonomer molar ratio. As expected, the T_g's of the N‐Z‐Hpr/DLMA copolymers were higher than the N‐Z‐Hpr/DLLA copolymers, the pendant groups on the monomers (N‐Z‐Hpr) became larger and more flexible, and the T_g's of the resulting polymers declined. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 724–731, 2001     

(3R,4S)‐3‐Phenyl‐1‐[(R)‐1‐phenyl­ethyl]‐4‐[(R)‐1‐phenylethyliminomethyl]azetidin‐2‐one

The configuration of the chiral ring atoms of the title compound, C₂₆H₂₆N₂O, obtained in an enantioselective synthesis, has been established relative to the known R configuration of the α‐methyl­benzyl moieties. The crystal packing involves a two‐dimensional network of C—H?π interactions between the aromatic rings.     

The Astounding Chemistry of a 2‐Amino‐1,2‐dihydroisoquinoline Derivative

The cycloadducts of isoquinolinium N‐phenyl imide 2 with C=C bonds are derivatives of 2‐amino‐1,2‐dihydroisoquinoline. Their N^β‐vinylphenylhydrazine system is amenable to an acid‐catalyzed [3,3]‐sigmatropic shift; the formation of pentacyclic aminals is exemplified by 6 → 8 . The dimethyl maleate adduct 11 , C₂₁H₂₀N₂O₄, is exceptional by being converted on treatment with acid to bright‐yellow crystals, C₂₄H₂₂N₂O₆ (additional C₃H₂O₂). X‐Ray crystal‐structure analysis and NMR spectra reveal structure 13 , and mechanistic studies indicated an initial β‐elimination at the N−N bond of 11 to yield 18 ; this step is followed by a retro‐Mannich‐type cleavage that gives methyl isoquinoline‐1‐acetate ( 14 ) and methyl 2‐(phenylimino)acetate ( 15 ), according to the sequence C₂₁H₂₀N₂O₄ ( 11 )→ 18 →C₁₂H₁₁NO₂ ( 14 )+C₉H₉NO₂ ( 15 ). In the second act of the drama, electrophilic attack by 15 ‐H⁺ on the ene‐hydrazine group of a second molecule of 11 furnishes 13 by a polystep intramolecular redox reaction. All rate constants must be fine‐tuned in this reaction cascade to give 13 in yields of up to 78% with an overall stoichiometry: 2 C₂₁H₂₀N₂O₄ ( 11 )→C₂₄H₂₂N₂O₆ ( 13 )+C₁₂H₁₁NO₂ ( 14 )+aniline. Interception and model experiments confirmed the above pathway. A by‐product, C₃₃H₃₁N₃O₆ ( 62 ), arises from an acid‐catalyzed dimerization of 11 and subsequent elimination of 15 .     

Synthesis of optically active af‐(1‐Ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and N‐(1‐Ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)pyridine‐3‐carboxamides

As part of the structure‐activity relationship of the dopamine D₂ and serotonin 5‐HT₃ receptors antagonist 1, which is a clinical candidate with a broad antiemetic activity, the synthesis and dopamine D₂ and serotonin 5‐HT₃ receptors binding affinity of (R)‐5‐bromo‐N‐(1‐ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and (R)‐5‐bromo‐N‐(1‐ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxam‐ides ( 2 and 3 ) are described. Treatment of 1‐ethyl‐2‐(p‐toluenesulfonyl)amino‐3‐methylaminopropane dihy‐drochloride ( 4a ) with paraformaldehyde and successive deprotection gave the 5‐aminohexahydro‐1,3‐diazine 6 in excellent yield. 3‐Amino‐1‐ethyl‐5‐methyloctahydro‐1,5‐diazocine ( 15 ) was prepared from 2‐(benzyloxycarbonyl)amino‐3‐[[N‐(tert‐butoxycarbonyl)‐N‐methyl]amino]‐1‐ethylaminopropane ( 9 ) through the intramolecular amidation of (R)‐3‐[N‐[(2‐benzyloxycarbonylamino‐3‐methylamino)propyl]‐N‐ethyl]aminopropionic acid trifluoroacetate ( 12 ), followed by lithium aluminum hydride reduction of the resulting 6‐oxo‐1‐ethyl‐5‐methyloctahydrodiazocine ( 13 ) in 41% yield. Reaction of the amines 6 and 15 with 5‐bromo‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxylic acid furnished the desired 2 and 3 , which showed much less potent affinity for dopamine D₂ receptors than 1 .