Synthesis of cyclic dimeric methyl morpholinoside—a common synthetic precursor to cyclic dinucleotide analogs

An eight-step synthesis of cyclic dimeric methyl morpholinoside (c-di-MM), a common synthetic precursor to a number of cyclic dinucleotide analogs is reported. The synthesis of c-di-MM proceeds through a morpholine monomer prepared from readily available inexpensive starting materials and culminates with a key macrolactamization reaction to provide the macrocycle in 15% overall yield.     

Synthesis of indeno-fused derivatives of quinolizinium salts, imidazo[1,2-a]pyridine, pyrido[1,2-a]indole, and 4h-quinolizin-4-one via benzannulated enyne-allenes

The benzannulated enediynyl propargylic alcohol 8 was prepared from 1-bromo-2-iodobenzene by two consecutive Sonogashira cross-coupling reactions. The subsequent transformation to mesylate 9 followed by treatment with 4-substituted pyridines 10 then furnished the benzannulated enediynes 11. On exposure of 11 to triethylamine, the indeno-fused quinolizinium salts 15 were produced in quantitative yield. Presumably the reaction proceeded through a 1,3-prototropic rearrangement to form the benzannulated enyne-allenes 12, which then underwent either a concerted Diels-Alder reaction or a two-step process involving a Schmittel cyclization reaction to form biradical 13 followed by an intramolecular radical-radical coupling to afford 14. A subsequent prototropic rearrangement then produced 15. Similarly, 21a and 21b were produced from 19a and 19b, respectively. The use of the Sonogashira reaction for cross-coupling between 1-iodo-2-(phenylethynyl)benzene (7) and 1-(2-propynyl)-1H-imidazole (25) followed by treatment of the resulting adduct with potassium tert-butoxide gave the indeno-fused imidazo[1,2-a]pyridine 24 in 98% yield. Similarly, the indeno-fused pyrido[1,2-a]indole 32 and 4H-quinolizin-4-one 35 were obtained by starting from 7 for cross-coupling with 1-(2-propynyl)-1H-indole (30) and 1-(2-propynyl)-2(1H)-pyridinone (33), respectively, followed by treatment with potassium tert-butoxide.     

An efficient synthesis of cyclic IDP- and cyclic 8-bromo-IDP-carbocyclic-riboses using a modified Hata condensation method to form an intramolecular pyrophosphate linkage as a key step. An entry to a general method for the chemical synthesis of cyclic ADP-ribose analogues

An efficient synthesis of cyclic IDP-carbocyclic-ribose (3) and its 8-bromo derivative 6, as stable mimics of cyclic ADP-ribose, was achieved, and a condensation reaction with phenylthiophosphate-type substrate 15 or 16 to form an intramolecular pyrophosphate linkage was a key step. N-1-Carbocyclic-ribosylinosine derivative 28 and the corresponding 8-bromo congener 24 were prepared via condensation between N-1-(2,4-dinitrophenyl)inosine derivative 17 and a known optically active carbocyclic amine 18. Compounds 24 and 28 were then converted to the corresponding 5"-phosphoryl-5'-phenylthiophosphate derivatives 15 and 16, respectively, which were substrates for the condensation reaction to form an intramolecular pyrophosphate linkage. Treatment of 8-bromo substrate 15 with I2 or AgNO3 in the presence of molecular sieves 3A (MS 3A) in pyridine at room temperature gave the desired cyclic product 12 quantitatively, while the yield was quite low without MS. The similar reaction of 8-unsubstituted substrate 16 gave the corresponding cyclized product 32 in 81% yield. Acidic treatment of these cyclic pyrophosphates 12 and 32 readily gave the targets 6 and 3, respectively. This result suggests that the construction of N-1-substituted hypoxanthine nucleoside structures from N-1-(2,4-dinitrophenyl)inosine derivatives and the intramolecular condensation by activation of the phenylthiophosphate group with I2 or AgNO3/MS 3A combine to provide a very efficient route for the synthesis of analogues of cyclic ADP-ribose such as 3 and 6. Thus, this may be an entry to a general method for synthesizing biologically important cyclic nucleotides of this type.     

Solid-phase synthesis of an A-B loop mimetic of the Cepsilon3 domain of human IgE: macrocyclization by Sonogashira coupling

The solid-phase synthesis of a cyclic peptide containing the 21-residue epitope found in the A-B loop of the Cepsilon3 domain of human immunoglobulin E has been carried out. The key macrocyclization step to form the 65-membered ring is achieved in approximately 15% yield via an "on-resin" Sonogashira coupling reaction which concomitantly installs a diphenylacetylene amino acid conformational constraint within the loop.     

Intramolecular electronic interactions in conjugated ferrocene-pi-extended-tetrathiafulvalene donor-pi-donor molecular hybrids

The synthesis of new hybrid ferrocene and pi-extended tetrathiafulvalene (TTF) donor(1)-pi-donor(2) molecular assemblies 16a-c has been carried out by a Wittig-Horner reaction of the respective phosphonate esters 15a-c with 2-(2-ferrocenylvinyl)-9, 10-anthraquinone (18) prepared by olefination of ferrocenecarboxaldehyde (14) and the anthraquinone phosphonium salt 17. Electrochemical studies show that the D(1)-pi-D(2) (D = donor) molecular assemblies 16a-c essentially retain the redox characteristics of both ferrocene and the pi-extended TTF components and the effects of solvent, temperature, scan rate, and working electrode are significant. Most importantly, pronounced intramolecular electronic interactions between the two donor moieties were observed by cyclic voltammetry and Osteryoung square wave voltammetry in both the ground and charged states. Semiempirical calculations support the electrochemical observations.     

Total synthesis of the ristocetin aglycon

The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular S(N)Ar reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degrees C, 8 h, DMF, >/=95%) and diastereoselective (>/=15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.     

CyClick Chemistry for the Synthesis of Cyclic Peptides

Here, we report a novel “CyClick” strategy for the macrocyclization of peptides that works in an exclusively intramolecular fashion thereby precluding the formation of dimers and oligomers via intermolecular reactions. The CyClick chemistry is highly chemoselective for the N‐terminus of the peptide with a C‐terminal aldehyde. In this protocol, the peptide conformation internally directs activation of the backbone amide bond and thereby facilitates formation of a stable 4‐imidazolidinone‐fused cyclic peptide with high diastereoselectivity (>99 %). This method is tolerant to a variety of peptide aldehydes and has been applied for the synthesis of 12‐ to 23‐membered rings with varying amino acid compositions in one pot under mild reaction conditions. The reaction generated peptide macrocycles featuring a 4‐imidazolidinone in their scaffolds, which acts as an endocyclic control element that promotes intramolecular hydrogen bonding and leads to macrocycles with conformationally rigid turn structures.     

Synthesis and reactions of heterocyclic methyl 2-propenoates and 2,3-epoxypropanoates with nucleophiles

Reaction of 2-(3-,4-)pyridinecarboxaldehydes 5 with carbomethoxymethylene triphenylphosphorane afforded predominantly E-methyl-3-(pyridinyl)-2-propenoates 7. Oxidation of 7a-c with m-chloroperbenzoic acid gave methyl E-3-(1-oxidopyridinyl)-2-propenoates 8a-c in high yield. The Darzen's reaction of 5a-c with methyl bromoacetate yielded a mixture of stereoisomers cis- 9a-c and methyl trans-3-(pyridinyl)-2,3-epoxy-propanoates 10a-c in a ratio of 2:1. Oxidation of cis- 9a-c and trans- 10a-c afforded the corresponding cis- 11a-c and methyl trans-3-(1-oxidopyridinyl)-2,3-epoxypropanoates 12a-c in good yield. The reaction of 11a and 12a with cyclic amines as piperidine gave the respective threo- 13 and methyl erythro-2-(1-piperidino)-3-hydroxy-3-(1-oxido-2-pyridino)propanoate 14. The sodium borohydride reduction of the N-alkoxylcarbonyl pyridinium salts of 9c and 10c afforded the corresponding N-alkoxycarbonyl-1,2-dihydropyridyl derivatives 15 and 16. A number of selected compounds ( 7a-c , 9a-c , 10a , 10c , 11a-c and 12a , 12c ) were found to be inactive in the P388 Lymphocytic screen. Compounds 9-12 did not react with the model nucleophile ethanethiol in phosphate buffer at 37°.     

Synthesis of cyclic peptidosulfonamides by ring-closing metathesis

N-Protected beta-aminoethanesulfonyl chlorides (2a-e) were used in the preparation of sulfonamides 4, 8, 11a-c, and 15. Ring-closing metathesis of sulfonamides 4 and 8 did not lead to the expected nine-membered cyclic peptidosulfonamides. In contrast, the allylated peptidosulfonamides 11a-c and 15 turned out to be suitable precursor systems for ring-closing metathesis using second-generation Grubbs catalyst and nine-membered cyclic peptidosulfonamides were obtained in 47-60% yields. The possibility for incorporation of these cyclic peptidosulfonamides into a peptide sequence was illustrated by the incorporation of an amino acid on the "S"- or "N"-terminus leading to 16 and 18-20, respectively. A model of cyclic peptidosulfonamide 16 hints at an extended-like structure.     

Preparation of a variety of macrocyclic Di- and tetraamides and their peraza-crown analogs using the crab-like cyclization reaction

Twelve new macrocyclic di- and tetraamides have been synthesized from the reaction of a bis(α-chloroamide) with a primary amine or with a diamine. Some of these cyclic di- and tetraamides contained pendant aminoalkyl groups attached on one or more ring nitrogen atoms. Two macrocyclic dithiadiamides were prepared from the reaction of a bis(α-chloroamide) and a dimercaptan. In every case, 12-, 14- and 15-membered cyclic di- and tetraamides were isolated in good yields. The 9-, 17- and 18-membered macrocycles were prepared in lower yields. Four of the amide-containing macrocycles were reduced by diborane to the perazacrown compounds.     

Carbon networks based on dehydrobenzoannulenes. 4. Synthesis of "star" and "trefoil" graphdiyne substructures via sixfold cross-coupling of hexaiodobenzene

The synthesis and characterization of star- and trefoil-shaped polyethynyl aromatic structures, which represent model substructures of the all-carbon network graphdiyne, are described. Assembly of these macrocycles is accomplished via 6-fold Sonogashira cross-coupling of hexaiodobenzene using Pd[P(o-Tol)(3)](2) and CuI as the catalytic system. The development of these modified Sonogashira conditions is detailed. This work has led to the synthesis of a new family of hexakis(phenylbutadiynyl)benzene derivatives (4a-c), the largest of which is the D(3)(h)()-symmetric "trefoil" 2 and is composed of three [18]annulenes fused at a common benzene ring. Attempts at the synthesis of "wheel" 3 are also described. Compound 2 represents the largest fragment of the graphdiyne network to date. UV-vis spectroscopic studies indicate enhanced electron delocalization throughout the extended pi-system.     

Stereoselective synthesis of allyl-C-mannosyl compounds: use of a temporary silicon connection in intramolecular allylation strategies with allylsilanes

Methyl mannoside 16 containing an allyldimethylsilyl ether at C(2) was synthesized in nine steps from D-mannose. Reaction with TMSOTf in MeCN at room-temperature effected C-glycosylation to provide the alpha-allyl-C-mannosyl product 18 with excellent stereoselectivity. Crossover experiments over a range of reaction concentrations proved that reaction was proceeding via an intermolecular pathway rather than the hoped-for intramolecular delivery route. The exceptionally high stereoselectivity of this allylation in the presence of an acid-scavenger, 2,6-DTBMP, can be attributed to the allylsilyl ether 16 behaving as the allylating agent. Geometrical constraints in the seven-membered ring transition state account for the lack of intramolecular allyl transfer. Attaching a modified allylsilane 29a-c to C(2)OH of methyl mannoside 15 improved matters. Reaction of the tethered mannosides 27a-c with TMSOTf in the presence of 2,6-DTBMP in MeCN at rt provided a range of products, which depended on the size of the alkyl substituents at the silyl ether tether. Diene products were the major compounds irrespective of the size of the alkyl substituents at the silyl ether tether. Their formation can be understood by intramolecular allylation of the allylsilane on to the activated anomeric center, followed by collapse of the intermediate carbocation by preferential attack of an external nucleophile at the silyl ether tether, rather than at the allylic silicon center. A cascade of further reactions rationalizes the formation of the 2-dienyl-substituted tetrahydrofuran 30 and dienes 39 and 40. The desired beta-allyl-C-mannosyl products 42 and 43 were obtained, albeit in low yield, when bulky ethyl and isopropyl groups were employed at the silyl ether tether. Stereospecific oxidative cleavage of the silyl tether in 42 and 43 provided the corresponding stereodefined diols 44 and 45, respectively. Attempts to improve the yield and diastereoselectivity of the desired beta-allyl-C-mannosyls by moving to a sulfoxide mannosyl donor, which could be activated at low temperature, proved unsuccessful.     

Convergent approach to the maduropeptin chromophore: aryl ether formation of (R)-3-aryl-3-hydroxypropanamide and cyclization of macrolactam

Efficient enantioselective syntheses of the functionalized phenol and diethynylcyclopentene moiety of the maduropeptin chromophore were achieved. Their CsF-mediated coupling yielded a sterically congested aryl propargyl ether. The subsequent intramolecular Sonogashira coupling reaction between the vinyl iodide and diethynyl groups occurred at the appropriate position to yield a macrolactam, which was accompanied by Pd-mediated enyne-yne benzannulation.     

Sulfoximine version of double elimination protocol for synthesis of chiral acetylenic cyclophanes

A new strategy for constructing enantiopure acetylenic cyclophanes is described on the basis of one-pot double elimination reaction starting from dialdehydes and bis(sulfoximine)s. In this case, the conventional sulfone protocol affords poorer yields of the desired cyclophanes. Thus, arylene-ethynylene moieties with terminal sulfoximine or formyl functions are linked to binaphthyl cores and these building blocks are then subjected to double elimination reaction. The desired macrocycles are obtained in up to 35 % yield. The corresponding Sonogashira coupling fails to afford cyclophanes indicative of effectiveness of the double elimination methodology.     

Efficient solid-phase-based total synthesis of the bisintercalator TANDEM

[reaction: see text] In this article, the first solid-phase-based total synthesis of TANDEM, a synthetic analogue of triostin A, is described. In initial studies, the synthesis incorporated depsipeptide formation, introduction of chromophores, and disulfide bond formation on the solid phase, prior to a final solution-phase macrolactamization, to give the target molecule. Although pure TANDEM was obtained in an overall yield comparable to those for all syntheses to date, the yield of the final cyclization was low (11%). A more efficient approach involved removal from the solid phase prior to disulfide bond formation. The resulting linear peptide underwent macrolactamization under mild conditions and high dilution. Final disulfide bond formation was essentially quantitative and gave the target molecule, TANDEM, in an overall yield of 18%. The final compound was assessed for its ability to bind to 5'-TpA sequences on DNA by DNase I footprinting. This efficient synthesis sets the stage for a study of the structure-activity relationship of TANDEM and the natural product triostin A, with analogues containing "point mutations" at every site within the cyclic compounds.     

A one-pot,multi-component reaction cascade for the rapid synthesis of diversely functionalized heteroaryl methyl substrates

A novel one-pot, “green” protocol to rapidly access pharmaceutically relevant heteroaryl methyl substrates is described. This process allows for a tandem S_N2/Suzuki-Miyaura reaction or Sonogashira reaction across a breadth of chemical diversity with yields ranging between 31 and 87% for the tandem Suzuki-Miyaura process and 50–66% for the tandem Sonogashira process. This procedure tolerates S, N, and O heteroatom linkers and is amenable for both rapid and robust lead development screening. In addition, T-type and N-type calcium channel blocker (15) was synthesized in 43% yield using this methodology which stands as an improvement in both yield and reaction time of the previously reported synthesis. The one-pot protocol also allows for the inclusion of greater chemical diversity within the scaffold of 15.     

Demonstration of 14-20-membered intramolecular carbonyl ylides: diastereoselective synthesis of macrocycles incorporating spiro-indolooxiranes

A range of macrocycles (13-19-membered) possessing spiro-indolooxirane unit were synthesized with complete diastereoselectivity in good yield by the rhodium(II) acetate catalyzed reaction of substituted cyclic diazoamides in dry dichloromethane. The reaction proceeds via the formation of the corresponding macrocyclic carbonyl ylide followed by a con-rotatory electrocyclization process.     

Intramolecular Diels-Alder Reaction of Furans with Allenyl Ethers Followed by Phenylthio and Trialkylsilyl Groups Rearrangement

A new reaction involving an intramolecular Diels-Alder reaction of a furan diene with an allenyl ether dienophile followed by phenylthio group rearrangement was discovered. Treatment of the propargyl ethers 2a-c with t-BuOK in t-BuOH at 85 ° C gave the phenylthio group rearrangement products 5a-c and 6a-c . A reaction involving an intramolecular Diels-Alder reaction of a furan diene with an allenyl ether dienophile followed by trialkylsilyl group rearrangement is also demonstrated.     

Synthesis and properties of conjugated hybrid tetrathiafulvalene dimers

The synthesis of new hybrid tetrathiafulvalene (TTF) dimers (11a-c) has been carried out by a Wittig-Horner reaction of the respective phosphonate esters (10a-c) with 2-(tetrathiafulvalenylvinyl)-9, 10-anthraquinone (9) prepared by olefination of formyltetrathiafulvalene (7) and the phosphonium salt of anthraquinone 8. Electrochemical studies show that the dimers 11a-c mainly retain the electrochemical properties of both TTF and the pi-extended TTF components, and most importantly, intramolecular electronic interactions between the two moieties are observed by cyclic voltammetry and Osteryoung square wave voltammetry. Semiempirical PM3 calculations reveal an almost planar geometry for the TTF and the benzene ring connected through the vinyl spacer. These compounds can form stable charge-transfer complexes with 2, 3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) showing a stoichiometry of 1:3 (D:A). Attempts to electrocrystallize the dimeric donors with different counteranions are discussed.     

Synthesis of conformationally constrained cyclic peptides using an intramolecular sonogashira coupling

[Reaction: see text]. Small peptides having a 3-bromobenzyl group at the C-termini and n-alkynoyl group at the N-termini undergo a smooth copper-free intramolecular Sonogashira coupling reaction to afford the corresponding cyclic peptides in moderate yields. Scope and limitations of this macrocyclization is demonstrated with di-, tri-, and tetrapeptides.