Synthesis of 2-Substituted Furanonaphthoquinones Using Directed Metalation and Cross Coupling Reactions

A synthetic method for the preparation of C-2 substituted furanonaphthoquinones from ortholithium-benzamide and the 2-furan-carboxaldehyde derivative is described. Four 2-alkyl-furanonaphthoquinones and the 2-phenyl-substituted were prepared via phathalide. This route has been shown to be general application to the synthesis of furanonaphthoquinones.     

Synthesis of a C-2 Stapled Bis-Lexitropsin

A convenient synthesis method was developed for the preparation of C-stapled homodimeric bis-lexitropsins connected through the nitrogen atoms of the central pyrrole ring with a bis-methylene linker. This lexitropsin is designed as a standard for other bis-lexitropsins with longer chains in biological evaluation and NMR studies. The key step in this method is the treatment of ethyl 4-nitropyrrole-2-carboxylate with flame-dried potassium carbonate in DMF followed by the addition of 1,2-dibromoethane to form the 1,2-dipyrroloethane derivative.     

Synthesis of a C-2 Stapled Bis-Lexitropsin

Summary. A convenient synthesis method was developed for the preparation of C-stapled homodimeric bis-lexitropsins connected through the nitrogen atoms of the central pyrrole ring with a bis-methylene linker. This lexitropsin is designed as a standard for other bis-lexitropsins with longer chains in biological evaluation and NMR studies. The key step in this method is the treatment of ethyl 4-nitropyrrole-2-carboxylate with flame-dried potassium carbonate in DMF followed by the addition of 1,2-dibromoethane to form the 1,2-dipyrroloethane derivative.     

Parent,Unsubstituted Hemiporphycene: Synthesis and Properties

Among seven possible nitrogen‐in constitutional isomers of porphyrin only one, porphycene, has been obtained so far in the free, unsubstituted form. Herein, the synthesis of another isomer, parent hemiporphycene ( HPc ), and its thorough structural, spectral, photophysical, electrochemical, and theoretical characterization are reported. Most of the properties of HPc are intermediate between those of porphyrin and porphycene, as evidenced by the values of inner‐cavity dimensions, orbital‐energy splittings, absorption coefficients, magnetic circular dichroism parameters, NH‐stretching frequencies, fluorescence quantum yields, tautomerization rates, and redox potentials. The largest differences arise with respect to tautomerism, due to the low symmetry of HPc and inequivalence of the four nitrogen atoms that define the inner cavity. Two trans tautomers are observed, separated in energy by about 1 kcal mol^?1. Tautomerization from the higher‐ to the lower‐energy form is detected in the lowest‐excited singlet state and occurs at a rate that is about four orders of magnitude lower than that observed for porphycene. Hemiporphycene is a very good model for the investigation of inequivalent intramolecular H‐bonds present in one molecule; two such bonds in HPc reveal unusual characteristics, and the bond strength results from the interplay between the N ??? N distance and the N?H?N angle.     

Synthesis and Antitumor Activity of C-2／C-10 Modified Analogues of Docetaxel

Four 10-propionyl docetaxel analogues (lla-d) with 2α-amido substituents were prepared, and their antitumor activity against three solid tumor cell lines and their drug-resistant counterparts were determined.     

Synthesis and biological properties of C-2 triazolylinosine derivatives

O(6)-(Benzotriazol-1H-yl)guanosine and its 2'-deoxy analogue are readily converted to the O(6)-allyl derivatives that upon diazotization with t-BuONO and TMS-N(3) yield the C-2 azido derivatives. We have previously analyzed the solvent-dependent azide·tetrazole equilibrium of C-6 azidopurine nucleosides, and in contrast to these, the O(6)-allyl C-2 azido nucleosides appear to exist predominantly in the azido form, relatively independent of solvent polarity. In the presently described cases, the tetrazole appears to be very minor. Consistent with the presence of the azido functionality, each neat C-2 azide displayed a prominent IR band at 2126-2130 cm(-1). A screen of conditions for the ligation of the azido nucleosides with alkynes showed that CuCl in t-BuOH/H(2)O is optimal, yielding C-2 1,2,3-triazolyl nucleosides in 70-82% yields. Removal of the silyl groups with Et(3)N·3HF followed by deallylation with PhSO(2)Na/Pd(PPh(3))(4) gave the C-2 triazolylinosine nucleosides. In a continued demonstration of the versatility of O(6)-(benzotriazol-1H-yl)purine nucleosides, one C-2 triazolylinosine derivative was converted to two adenosine analogues via these intermediates, under mild conditions. Products were desilylated for biological assays. The two C-2 triazolyl adenosine analogues demonstrated pronounced antiproliferative activity in human ovarian and colorectal carcinoma cell cultures. When evaluated for antiviral activity against a broad spectrum of DNA and RNA viruses, some of the C-2 triazolylinosine derivatives showed modest inhibitory activity against cytomegalovirus.     

Synthesis of novel C-2 substituted pyrimidine nucleoside analogs

A series of 2-(2-oxoalkylidene)-4(1H)-pyrimidinone nucleoside analogs were synthesized by the addition of the lithium enolates of methylketones to 2,5′- and 2,2′-anhydrouridines and to 2,5′-anhydrothymidines. Alternatively, 2-thiouridine was alkylated with bromomethyl ketones to yield 2-(2-oxoalkyl)thio-4(1H)-pyrimidinone ribofuranosides in good yields. These intermediates were subsequently transformed into the title compounds via an Eschenmoser sulfur extrusion reaction. The 2-(2-oxoalkylidene)-4-(1H)-pyrimidinone nucleoside analogs exhibit enol proton signals in their ¹H nmr spectra indicative of hydrogen bonding between N-3 and keto oxygen. These structures offer functional groups with potential for Watson-Crick hydrogen bonding.     

Beyond p-Hexaphenylenes: Synthesis of Unsubstituted p-Nonaphenylene by a Precursor Protocol

The synthesis of unsubstituted oligo-para-phenylenes ( OPP ) exceeding para-hexaphenylene—in the literature often referred to as p-sexiphenyl—has long remained elusive due to their insolubility. We report the first preparation of unsubstituted para-nonaphenylenes ( 9PP s) by extending our precursor route to poly-para-phenylenes ( PPP ) to a discrete oligomer. Two geometric isomers of methoxylated syn- and anti-cyclohexadienylenes were synthesized, from which 9PP was obtained via thermal aromatization in thin films. 9PP was characterized via optical, infrared and solid-state ¹³C NMR spectroscopy as well as atomic force microscopy and mass spectrometry, and compared to polymeric analogues. Due to the lack of substitution, para-nonaphenylene, irrespective of the precursor isomer employed, displays pronounced aggregation in the solid state. Intermolecular excitonic coupling leads to formation of H-type aggregates, red-shifting emission of the films to greenish. 9PP allows to study the structure–property relationship of para-phenylene oligomers and polymers, especially since the optical properties of PPP depend on the molecular shape of the precursor.     

Synthesis of some novel C-2 derivatives in the tetracycline series

The 2-ethoxycarbonyl-2-decarboxamidodoxycycline

has been achieved starting from doxycyclinenitrile

. By reaction of doxycycline hydrochloride with P₂S₅ in dioxane it was obtained the 2-thiocarboxamido-2-decarboxamidodoxycycline

from which, with a Raney-Nickel reduction, it was possible to isolate the 2-methylamino-2-decarboxamidodoxycycline

.     

Unsubstituted bicyclo[1.1.0]but-2-ylcarbinyl cations

A synthesis for the unsubstituted bicyclo[1.1.0]but-2-ylmethanols (endo- and exo-9) from 1,3-butadiene has been developed. Solvolyses of their sulfonates 10 and 11 took entirely different courses, as the endo compound 10 gave rise exclusively to rearranged products such as cyclopent-3-en-1-ol (14), while the exo compound 11 underwent only the substitution of the tosylate group with complete retention of the exo-bicyclo[1.1.0]but-2-ylmethyl skeleton. Under solvolytic conditions, 10 reacted at very similar rates to the corresponding monocyclic substrate, that is, cyclopropylcarbinyl mesylate (19); in contrast, 11 reacted only three times as fast as n-butyl tosylate and about 1000-fold slower than 10. The nature of the bicyclo[1.1.0]but-2-ylcarbinyl cations has been probed by quantum chemical calculations. Whereas, the exo isomer (exo-18) corresponds to a local energy minimum, the endo isomer is only a transition state [endo-18(TS)] for an automerization of the nonclassical cyclopent-3-en-1-yl cation (13) and converts into 13 by a Wagner-Meerwein rearrangement. The most favorable isomerization of exo-18 also leads to 13 but via a transition state resembling the 2-vinylcycloprop-1-yl cation [25(TS)]. On the introduction of methyl groups at positions 1 and 3 of exo-18, the cation is no longer an energy minimum and it becomes a transition state [27(TS)] for an automerization of the nonclassical 1,3-dimethylcyclopent-3-en-1-yl cation (28). The large effect of the methyl substitution rationalizes the puzzling results of the previous product and rate studies, which utilized various substituted derivatives of bicyclo[1.1.0]but-2-ylcarbinyl sulfonates as substrates.     

Total Synthesis of C-8-Geranylflavonoids

Geranylflavonoids are interesting natural products isolated in recent years from some traditional medicinal plants. Some of these flavanoids have been reported to exhibit hypotensive, antibacterial and antitumor effects¹. With respect to the synthesis of geranylflavonoids, only the 8-geranylflavanone skeleton as found in compounds 1², 2³ and 3⁴ has not been yet prepared.     

Efficient and Stereoselective Synthesis of C-(β-2''-Deoxynucleosides)

The formation of triplex DNA is, in principle, an effective way of regulating the expression of selected genes.[1]Many cytosine mimics were investigated to form triplex DNA, e.g., 2-amino-(2'-deoxy-β-D-ribofuranosyl)pyridine (9)was proved to have some effectiveness in stabilizing triplex DNA under neutral conditions.[2] Stereoselective synthesis of 9 was achieved starting from 2-deoxyribose.     

Synthesis of C-24 β-lactams of bile acids

Methyl 3α-hydroxy-5β-cholan-24-oate III and methyl 3α,12α-dihydroxy-5β-cholan-24-oate IV were converted into the respective hydrazides V and VI by reaction with hydrazine. These hydrazides were reacted with aryl aldehyde VII to give the corresponding 24-arylidene-hydrazides VIII and IX. The reaction of Schiff bases VIII and IX with monochloroacetyl chloride in the presence of triethylamine afforded β-lactams X-XI.     

Synthesis of Imidazole Derivatives Using 2‐Unsubstituted 1H‐Imidazole 3‐Oxides

The reaction of 1,4,5‐trisubstituted 1H‐imidazole 3‐oxides 1 with Ac₂O in CH₂Cl₂ at 0 – 5° leads to the corresponding 1,3‐dihydro‐2H‐imidazol‐2‐ones 4 in good yields. In refluxing Ac₂O, the N‐oxides 1 are transformed to N‐acetylated 1,3‐dihydro‐2H‐imidazol‐2‐ones 5 . The proposed mechanisms for these reactions are analogous to those for N‐oxides of 6‐membered heterocycles (Scheme 2). A smooth synthesis of 1H‐imidazole‐2‐carbonitriles 2 starting with 1 is achieved by treatment with trimethylsilanecarbonitrile (Me₃SiCN) in CH₂Cl₂ at 0 – 5° (Scheme 3).