Synthesis and incorporation into PNA of fluorinated olefinic PNA (F-OPA) monomers

[structure: see text] A fluorinated OPA monomer containing the base thymine ((Z)-t-F-OPA) was synthesized in 12 steps, featuring a highly selective allylic over homoallylic Mitsunobu substitution for the introduction of the nucleobase. F-OPA modified PNA decamers were prepared by the MMTr/acyl protection strategy. The thermal stability of duplexes of PNA decamers containing (Z)-t-F-OPA units with antiparallel complementary DNA was measured. We found a strong dependence of stability from the sequential position of the (Z)-t-F-OPA units, ranging from DeltaT(m) of +2.4 to -8.1 degrees C/modification relative to unmodified PNA.     

High-yield synthesis of pyrrolidinyl PNA monomers

Two monomers for the syntheses of conformationally restricted peptide nucleic acids were synthesized through a simple procedure, involving an asymmetric 1,3-dipolar cycloaddition chemistry as a key step, from common starting materials in 3 and 5 steps, and 58.8% and 30.5% overall yields, respectively.     

Synthesis of hydrazino-peptide nucleic acid monomers and dimers as new PNA backbone building blocks

We describe the synthesis of new hydrazinoPNA (hydPNA) monomers and new hydPNA-containing dimers. For the hydPNA monomers, the primary terminal amino group of the aminoethylglycine unit of classical aegPNA is replaced by a hydrazine moiety. An appropriate choice of two orthogonal protecting groups on the two hydrazine nitrogen atoms makes it possible to drive their coupling with other monomers selectively on one or the other nitrogen atom, thus obtaining two different types of PNA dimers. These dimers represent new building blocks that can be used to generate novel PNA oligomers.     

Synthesis of chiral chromium tricarbonyl labeled thymine PNA monomers via the Ugi reaction

[reaction: see text] Ugi condensation was used to synthesize the first examples of chiral racemic Ar.Cr(CO)(3) labeled peptide nucleic acid (PNA) monomers bearing the organometallic moiety linked to the alpha-carbon of the glycine unit.     

Synthesis and oligomerization of Fmoc/Boc-protected PNA monomers of 2,6-diaminopurine, 2-aminopurine and thymine

A Boc-protecting group strategy for Fmoc-based PNA (peptide nucleic acid) oligomerization has been developed for thymine, 2,6-diaminopurine (DAP) and 2-aminopurine (2AP). The monomers may be used interchangeably with standard Fmoc PNA monomers. The DAP monomer was incorporated into a PNA and was found to selectively bind to T (ΔT(m)≥ +6 °C) in a complementary DNA strand. The 2AP monomer showed excellent discrimination of T (ΔT(m)≥ +12 °C) over the other nucleobases. 2AP also acted as a fluorescent probe of the PNA:DNA duplexes and displayed fluorescence quenching dependent on the opposite base.     

Synthesis of amino-5-arylsulfonylpyrimidines

Several new 4-amino-5-arylsulfonylpyrimidines were prepared via the reaction of various α-(ethoxymethylene)arylsulfonylacetonitriles with guanidine or variously substituted amidines (Table II). 2,4-Diamino-5-(p-chlorophenylsulfonyl)pyrimidine (IIIg), a typical example, was prepared from the reaction of 2-(p-chlorophenylsulfonyl)-3-ethoxyacrylonitrile (IId) with guanidine in refluxing ethanol containing sodium ethoxide. With proper substitution of the ethoxymethylene intermediate, the method was found suitable for the preparation of other compounds having either a hydroxy or methyl group at the 4-position of the 5-arylsulfonylpyrimidine. The fluoro group in 2,4-diamino-5-(p-fluorophenylsulfonyl)pyrimidine (IIIx) was successfully replaced by nucleophilic reagents such as sodium ethoxide, N-methylpiperazine and N,N-diethylethylene-diamine. Attempts at direct displacement of fluorine by ammonia at 190° were unsuccessful.     

Synthesis of pyrrolidinone PNA: a novel conformationally restricted PNA analogue

To preorganize PNA for duplex formation, a new cyclic pyrrolidinone PNA analogue has been designed. In this analogue the aminoethylglycine backbone and the methylenecarbonyl linker are connected, introducing two chiral centers compared to PNA. The four stereoisomers of the adenine analogue were synthesized, and the hybridization properties of PNA decamers containing one analogue were measured against complementary DNA, RNA, and PNA strands. The (3S,5R) isomer was shown to have the highest affinity toward RNA, and to recognize RNA and PNA better than DNA. The (3S,5R) isomer was used to prepare a fully modified decamer which bound to rU10 with only a small decrease in Tm (delta Tm/mod = 1 degree C) relative to aminoethylglycine PNA.     

Synthesis of a ferrocenyl uracil PNA monomer for insertion into PNA sequences

The deprotection of the tert-butyl group of a ferrocenyl uracil Peptide Nucleic Acid (PNA) monomer, Fmoc-aeg(R)-O^tBu (1) was achieved using a two step synthesis involving hydrolysis in basic conditions to give first the zwitterion of ⁺NH₃-aeg(R)-O⁻ (7). Compound 7 was reacted in situ with N-(9-fluorenylmethoxycarbonyloxy)succinimide to obtain the expected compound Fmoc-aeg(R)-OH (2) (Abbreviations: Aeg = (2-aminoethyl)-glycine; Fmoc = 9-fluorenylmethoxycarbonyl; O^tBu = tert-butyl; R = 5-(N-ferroce-nylmethylbenzamido)uracyl).     

Synthesis of a C-linked glycosylated thymine-based PNA monomer and its incorporation into a PNA oligomer

Backbone modification of peptide nucleic acids (PNAs) by glycosylation has been shown to enhance selective biodistribution and cellular targeting of PNA oligomers based on sugar and cell surface lectin interactions. Here we report the synthesis of a new backbone-glycosylated thymine-based PNA monomer (T(gal)). The sugar residue was attached to the backbone of PNA via a stable carbon-carbon linkage between the sugar and the PNA monomers. Also, incorporation of the modified monomer into a PNA decamer (H-Ala(gal)-G-G-G-T(gal)-C-A-G-C-T(gal)-T-Lys-NH2) was successfully performed. Melting temperature (UV-Tm) of the modified PNA against the complementary DNA was only slightly lower than unmodified PNA.     

Synthesis of aminimide monomers and polymers

A convenient and practical synthesis of trimethylamine acrylimide, 1 , starting from 1, 1, 1-trimethylhydrazinium p-toluenesulfonate, 3 , and 3-chloropropionyl chloride is described. The intermediate, trimethylamine 3-chloropropionimide, 2 , is easily transformed into 1 either through a single-step dehydrohalogenation or through a two-step process consisting of very facile thermal rearrangement to 1,1,1-trimethylacrylylhydrazinium chloride, 4 , and subsequent deprotonation. Two new polymerizable monomers, 5 , and 6 , containing aminimide functionality were synthesized from trimethylamine imine, 7 , and the appropriate vinyl oxazolones, 8 , and 9 . Synthesis of hitherto unreported trimethylamine chloroacetimide, 10 , which offers unique opportunities for incorporating water-solubilizing and alkali-stable aminimide functionality into a variety of structures through nucleophilic displacement, is also described.     

Synthesis and reactivity of metal-containing monomers

The polymerization of diacrylates of the nontransition metals Mg, Zn, Ba, and Pb, which proceeds at low temperatures (5–10°C) with the complexes of alkylcobalts with tridentate Shiff bases (RCo) as initiators, was studied. The radical mechanism of the process was proved with the aid of free radical scavengers. The polymerization kinetics is given by the equationW _n = k [M] · [RCo]^0.75. The influence of the nature of the metal in the monomer and the alkyl ligand in the initiator on the polymerization process was discussed. Low temperatures promote the formation of polymers with high molecular weights and a predominantly syndiotactic structure. The effect of the steric hindrances arising during polymerization due to the formation of a three-dimensional cross-linked structure in the metal-containing polymer on the microstructure of polymer chain and on polymerization kinetics was considered.For part 24 seeBull. Acad. Sci., Div. Chem. Sci., 1992, 1609.For a preliminary communication see Ref.1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 500–503, March, 1993.     

Rapid access with diversity to enantiopure flexible PNA monomers following asymmetric orthogonal strategies

Different synthetic procedures are described in the rapid elaboration of flexible PNA monomers based on the 6-amino-8-base-octanoate and 5-amino-7-base-heptanoate scaffolds. Asymmetric Aza-Michael monoaddition is successfully applied to starting materials derived from sebacic/azelaic long-chain diacids and 6-membered oxacyclohexane commercial derivatives. Chain length, orthogonality of the ester functionalities, and Z/E isomerism of these prime substrates yielded high-valuable multifunctional intermediates through this asymmetric conjugate addition. Key features are the diversity toward PNA monomer synthesis, orthogonal chemoselective transformations, and Mitsunobu nucleobase substitution as an exceptional approach to introduce nucleobases in the final step.     

Synthesis and reactivity of metal-containing monomers

Thermal transformations of Fe^III maleate, [Fe₃O(OOCCH=CHCOOH)₆]OH·3H₂O (1), in an autogenerated atmosphere and the change in the short-range surrounding of Fe atoms during thermolysis were studied. The thermal transformations of1 are accompanied by the following processes: dehydration with simultaneous rearrangement of the ligand environment and formation of maleic acid, and polymerization of the rearranged monomer and its decarboxylation at high temperatures. In the initial stage of decarboxylation, the destruction of the metal-carboxylate Fe₃O complex occurs followed by the formation of the Fe−Fe bond (r=0.246 nm). The oxidation of the Fe atoms is observed when the thermolysis duration increases. For Part 49, seeIzv. Akad. Nauk, Ser. Khim., 1998; 1145 [Russ. Chem. Bull., 1998,47, 1113 (Engl. Transl.)]. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1505–1510, August, 1998.     

Synthesis and reactivity of metal-containing monomers

The reaction of Rh₆(CO)₁₅MeCN with allyldiphenylphosphine under mild conditions afforded the cluster-containing complex [Rh₆(CO)₁₄(μ,η²-PPh₂Ch₂CH=CH₂)]. Its molecular structure was characterized. The resulting complex is an octahedral Rh cluster with ten terminal and four μ₃-bridging CO ligands. The average Rh?Rh distance is 2.762(2) Å. The unsaturated ligand is additionally coordinated to the metal center (Rh(4)–C(232), 2.37(1) Å; and Rh(4)–C(233), 2.32(2) Å) to form a π-bond.     

Synthesis and reactivity of metal-containing monomers

Optically active mixed alkoxy orthotitanates with general formula Ti(OR¹)₂(OR²)(OR³) (R¹=Et, Buⁿ; R²=CH₂CH₂OCOC(Me)=CH₂; R³=menthyl, CH(Me)CH₂Me, CH(Ph)CH(NHMe)Me, CH(C₉H₆N)(C₉H₁₄N)) were obtained for the first time by transesterification. The Ti^IV monomers synthesized were characterized by elemental analysis, ozonolysis, and¹H and¹³C NMR and IR spectroscopy. Polymer products with optical activity were obtained by liquid phase radical copolymerization of Ti^IV-containing monomers. For Part 51, see Ref. 1. Deceased. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1739–1743, September, 1999.