Synthesis of a Bent, Twisted, and Chiral Phenanthrene via an Iodine Monochloride-Mediated, Strain-Inducing π-Extension Reaction.

A strategy for the synthesis of substituted and strained p-phenylene units is reported. An oxidative allylic alcohol rearrangement, followed by organometallic addition to the resulting α-ketol and subsequent dehydrative aromatization, affords p-terphenyl-containing macrocycles in which the central p-phenylene has been selectively substituted. Ten 18-membered macrocycles have been synthesized, eight of which contain substituents that could enable π-extension. Only alkynylated derivatives were amenable to π-extension via an ICl-mediated reaction, affording a highly bent, twisted, and chiral phenanthrene.

Carbamoyl Functionalized Bent para-Phenylenes via an Unexpected Reaction of the Burgess Reagent with α-Ketols.

The attempted dehydration of macrocyclic α-ketols with the Burgess reagent has resulted in the unexpected synthesis of carbamoylated, bent para-phenylene units. The same reaction with an acyclic analogue affords the intended dehydration product, indicating that the change in reactivity is conformationally controlled and a result of the bifunctional nature of the Burgess reagent.

A macrocycle directed total synthesis of di-O-methylendiandrin A.

The total synthesis of the lignan-based cyclobutane di-O-methylendiandrin A has been achieved using diastereoselective, vicinal alkylation and transannular McMurry reactions of a macrocyclic 1,4-diketone as key transformations for establishing relative stereochemistry and furnishing the strained 4-membered ring of the natural product.

π-Extension of Strained Benzenoid Macrocycles Using the Scholl Reaction.

A series of bent p-terphenyl-containing macrocycles have been synthesized and then regioselectively brominated, arylated, and subsequently subjected to a Scholl-based cyclodehydrogenation reaction. Shortening the alkyloxy bridging unit of these macrocycles increases the bend in the p-terphenyl unit, as well as the strain energy (SE) of the central para-phenylene ring system. For the first time, incremental increases in SE of the macrocyclic structure of this class of benzenoid compounds have been investigated in the context of π-extension to strained polycyclic aromatic hydrocarbon systems using the Scholl reaction.

Regioselective Synthesis of Unsymmetric Tetra- and Pentasubstituted Pyrenes with a Strategy for Primary C-Alkylation at the 2-Position.

The synthesis of 1,2,4,5- and 1,2,9,10-tetrasubstituted and 1,2,4,5,8-pentasubsutituted pyrenes has been achieved by initially functionalizing the K-region of pyrene. Bromination, acylation, and formylation reactions afford high to moderate levels of regioselectivity, which facilitate the controlled introduction of other functional groups about 4,5-dimethoxypyrene. Access to 4,5-dimethoxypyren-1-ol and 9,10-dimethoxypyren-1-ol enabled a rare, C-2 primary alkyl substitution of pyrene.

A Macrocyclic 1,4-Diketone Enables the Synthesis of a p-Phenylene Ring That Is More Strained than a Monomer Unit of [4]Cycloparaphenylene.

The synthesis of a p-terphenyl-based macrocycle, containing a p-phenylene unit with 42.6 kcal/mol of strain energy (SE), is reported. The conversion of a macrocyclic 1,4-diketone to a highly strained arene system takes place over five synthetic steps, featuring iterative dehydrative reactions in the aromatization protocol. Spectroscopic data of the deformed benzenoid macrocycle are in excellent agreement with other homologues that have been reported, indicating that the central p-phenylene ring of 9 is aromatic.

Overcoming Strain-Induced Rearrangement Reactions: A Mild Dehydrative Aromatization Protocol for Synthesis of Highly Distorted p-Phenylenes.

A series of p-terphenyl-based macrocycles, containing highly distorted p-phenylene units, have been synthesized. Biaryl bonds of the nonplanar p-terphenyl nuclei were constructed in the absence of Pd-catalyzed or Ni-mediated cross-coupling reactions, using 1,4-diketones as surrogates to strained arene units. A streamlined synthetic protocol for the synthesis of 1,4-diketo macrocycles has been developed, using only 2.5 mol % of the Hoveyda-Grubbs second-generation catalyst in both metathesis and transfer hydrogenation reactions. Under protic acid-mediated dehydrative aromatization conditions, the central and most strained benzene ring of the p-terphenyl systems was susceptible to rearrangement reactions. To overcome this, a dehydrative aromatization protocol using the Burgess reagent was developed. Under these conditions, no strain-induced rearrangement reactions occur, delivering p-phenylene units with up to 28.4 kcal/mol strain energy and deformation angles that sum up to 40°.

A non-cross-coupling approach to arene-bridged macrocycles: synthesis, structure, and direct, regioselective functionalization of a cycloparaphenylene fragment.

A new synthetic strategy that employs a relatively unstrained, 1,4-diketo-bridged macrocycle as a precursor to a strained, 1,4-arene-bridged (bent para-phenylene) macrocycle has been developed. The distorted p-terphenyl nucleus (CPP fragment) of the macrocycle has been characterized by X-ray crystallography, and a direct, regioselective bromination protocol of the macrocyclic system is reported.

Alternative syntheses of (S)-cEt-BNA: a key constrained nucleoside component of bioactive antisense gapmer sequences.

Approaches to the synthesis of the constrained 5-methyluracil nucleoside (S)-cEt-BNA, a key "gapmer" unit in a number of biologically relevant antisense oligonucleotides, are described using 5-methyluridine as starting material. In the shorter synthesis, a nine-step linear sequence afforded a O-protected (S)-cEt-BNA consisting of a [2.2.1]dioxabicycloheptane core in 7% overall yield. A competing reaction in an intramolecular cyclization of a tosylate led to a bicyclic oxetane.

A constrained tricyclic nucleic acid analogue of α-L-LNA: investigating the effects of dual conformational restriction on duplex thermal stability.

A constrained tricyclic analogue of α-L-LNA (2), which contains dual modes of conformational restriction about the ribose sugar moiety, has been synthesized and characterized by X-ray crystallography. Thermal denaturation experiments of oligonucleotide sequences containing this tricyclic α-L-LNA analogue (α-L-TriNA 2, 5) indicate that this modification is moderately stabilizing when paired with complementary DNA and RNA, but less stabilizing than both α-L-LNA (2) and α-L-TriNA 1 (4).

Synthesis of cis- and trans-α-l-[4.3.0]bicyclo-DNA monomers for antisense technology: methods for the diastereoselective formation of bicyclic nucleosides.

Two α-L-ribo-configured bicyclic nucleic acid modifications, represented by analogues 12 and 13, which are epimeric at C3' and C5' have been synthesized using a carbohydrate-based approach to build the bicyclic core structure. An intramolecular L-proline-mediated aldol reaction was employed to generate the cis-configured ring junction of analogue 12 and represents a rare application of this venerable organocatalytic reaction to a carbohydrate system. In the case of analogue 13, where a trans-ring junction was desired, an intermolecular diastereoselective Grignard reaction followed by ring-closing metathesis was used. In order to set the desired stereochemistry at the C5' positions of both nucleoside targets, a study of diastereoselective Lewis acid mediated allylation reactions on a common bicyclic aldehyde precursor was carried out. Analogue 12 was incorporated in oligonucleotide sequences, and thermal denaturation experiments indicate that it is destabilizing when paired with complementary DNA and RNA. However, this construct shows a significant improvement in nuclease stability relative to a DNA oligonucleotide.

1,1,n,n-Tetramethyl[n](2,11)teropyrenophanes (n = 7-9): a series of armchair SWCNT segments.

A new iterative bridge formation strategy has been employed in the synthesis of a series of [n](2,11)teropyrenophanes (n = 7-9). The generation of the nonplanar teropyrene system, which is calculated to be bent through 178.7° for the smallest homologue (n = 7), is accomplished using a VID reaction of a cyclophanemonoene precursor for the first time.

Structure-based design of a highly constrained nucleic acid analogue: improved duplex stabilization by restricting sugar pucker and torsion angle γ.

Dual conformational restriction: a new, highly constrained modification of the α-L-locked nucleic acid (α-L-LNA) scaffold that locks the sugar furanose ring in an N-type configuration and also restricts rotation around torsion angle γ was synthesized. This new modification increases the thermostability of an oligonucleotide duplex compared to using a single mode of constraint alone.

Interplay of pi-electron delocalization and strain in [n](2,7)pyrenophanes.

The geometries of a series of [n](2,7)pyrenophanes (n = 6-12) were optimized at the B3LYP/6-311G** DFT level. The X-ray crystal structures determined for the [9](2,7)- and [10](2,7)pyrenophanes agreed excellently with the computed structures. The degree of nonplanarity of the pyrene moiety depends on the number of CH2 groups in the aliphatic bridge and, as analyzed theoretically, influences the strain energy and the extent of pi-electron delocalization in the pyrene fragment. Various indices, e.g., the relative aromatic stabilization energies (DeltaASE), magnetic susceptibility exaltations (Lambda), nucleus-independent chemical shifts (NICS), and the harmonic oscillator model of aromaticity (HOMA) were used to quantify the change in aromatic character of the pyrene fragment. DeltaASE and relative Lambda values (with respect to planar pyrene) were evaluated by homodesmotic equations comparing the bent pyrene unit with its bent quinoid dimethylene-substituted analog. The bend angle, alpha, DeltaASE, and Lambda were linearly related. The aromaticity decreases smoothly and regularly over a wide range of bending, but the magnitude of the change is not large. The differences between planar pyrene (alpha = 0 degrees) and the most distorted pyrene unit (alpha = 39.7 degrees in [6](2,7)pyrenophane) are only 15.8 kcal/mol (DeltaASE) and 18.8 cgs-ppm (Lambda). Also, the geometry-based HOMA descriptor changes by only 0.07 unit. The local NICS descriptors of aromatic character also correlate very well with the global indices of aromaticity. In line with the known reactivity of pyrenophanes, the variations of NICS(1), a measure of pi-electron delocalization, were largest for the outer, biphenyl-type rings. The strain energies of the pyrene fragments were much larger and varied more than those evaluated for the bridge. Both strain energies were interrelated (correlation coefficient R = 0.979) and depend on the bend angle, alpha.

Benzo[a]acecorannulene: surprising formation of a new bowl-shaped aromatic hydrocarbon from an attempted synthesis of 1,2-diazadibenzo[d,m]corannulene.

[Structure: see text] Flash vacuum pyrolysis of 7,10-bis(2-bromophenyl)acenaphtho[1,2-d]pyridazine (C26H14Br2N2) has resulted in a surprising transformation, including dinitrogen loss, to give benzo[a]acecorannulene, a novel C26H12 bowl-shaped fullerene fragment.