Recent Advances in Transition Metal Catalyzed C-H Functionalization Reactions Involving Aza/Oxabicyclic Alkenes

Bicyclic alkenes, including Oxa- and azabicyclic alkenes can be readily activated by using transition-metal complexes with facial selectivity, because of the intrinsic angle strain on carbon-carbon double bonds of these unsymmetrical bicyclic systems. During last decades considerable progress has been done in the area of ring-opening of bicyclic strained ring by employing the concept of C-H activation. This Review comprehensively compiles the various C-H bond activation assisted reactions of oxa- and azabicyclic alkenes, viz., ring-opening reactions, hydroarylation as well as annulation reactions.

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

Since the first synthetic report in 2003 by Sakurai et al., sumanene (derived from the Indian ‘Hindi as well as Sanskrit word’ “Suman”, which means “Sunflower”), a beautifully simple yet much effective bowl-shaped C 3-symmetric polycyclic aromatic hydrocarbon having three benzylic positions clipped between three phenyl rings in the triphenylene framework has attracted a tremendous attention of researchers worldwide. Therefore, since its first successful synthesis, a variety of functionalized sumanenes as well as heterosumanenes have been developed because of their unique physiochemical properties. For example, bowl-to-bowl inversion, bowl depth, facial selectivity, crystal packing, metal complexes, intermolecular charge transfer systems, cation–π complexation, electron conductivity, optical properties and so on. Keeping the importance of this beautiful scaffold in mind, we compiled all the synthetic routes available for the construction of sumanene and its heteroatom derivatives including Mehta’s first unsuccessful effort up to the latest achievements. Our major goal to write this review article was to provide a quick summary of where the field has been, where it stands at present, and where it might be going in near future. Although several reviews have been published on sumanene chemistry dealing with different aspects but this is the first report that comprehensively describes the ‘all-in-one’ chemistry of the sumanene architecture since its invention to till date. We feel that this attractive review article will definitely help the scientific community working not only in the area of organic synthesis but also in materials science and technology.

Experimental and Computational Studies Unraveling the Peculiarity of Enolizable Oxoesters in the Organocatalyzed Mannich-Type Addition to Cyclic N-Acyl Iminium Ions

γ− and δ-Oxoesters are easily available starting materials that have been sparingly used in some organocatalyzed reactions proceeding with a high enantioselectivity. In our experimentation we found that the use of these compounds as the enolizable (nucleophilic) component in organocatalyzed Mannich-type reactions using in situ-generated cyclic N-acyl iminium ions gave low diastereoselectivity and low to moderate values of enantioselectivity. This significant drop of facial selectivity with respect to simple aliphatic aldehydes has been rationalized by means of density functional theory (DFT) calculations.

(±)-trans-1,2-Cyclohexanediamine-Based Bis(NHC) Ligand for Cu-Catalyzed Asymmetric Conjugate Addition Reaction

Bis(NHC) ligand precursors, L1, based on trans-1,2-diaminocyclohexane were designed and synthesized. To introduce chirality at the hydroxyamide side arm on the NHC of L1, a chiral β-amino alcohol, such as enantiopure leucinol, was used. Cu-catalyzed asymmetric conjugate addition reactions of cyclic and acyclic enones with Et2Zn were selected to evaluate the performance of L1 as a chiral ligand. For the reaction of cyclic enone, a combination of [bis(trimethylsilyl)acetylene]-(hexafluoroacetylacetonato)copper(I) (Cu(hfacac)(btmsa)) with a (±)-trans-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (rac; S,S)-L1, which was prepared from (S)-leucinol, was the most effective. Thus, treating 2-cyclohexen-1-one (3) with Et2Zn in the presence of catalytic amounts of Cu(hfacac)(btmsa) and (rac; S,S)-L1 afforded (R)-3-ethylcyclohexanone ((R)-4) with 97% ee. Similarly, use of (rac; R,R)-L1, which was prepared from (R)-leucinol, produced (S)-4 with 97% ee. Conversely, for the asymmetric 1,4-addition reaction of the acyclic enone, optically pure (−)-trans-1,2-cyclohexanediamine-based bis(NHC) ligand precursor, (R,R; S,S)-L1, worked efficiently. For example, 3-nonen-2-one (5) was reacted with Et2Zn using the CuOAc/(R,R; S,S)-L1 catalytic system to afford (R)-4-ethylnonan-2-one ((R)-6) with 90% ee. Furthermore, initially changing the counterion of the Cu precatalyst between an OAc and a ClO4 ligand on the metal reversed the facial selectivity of the approach of the substrates. Thus, the conjugate addition reaction of 5 with Et2Zn using the Cu(ClO4)2/(R,R; S,S)-L1 catalytic system, afforded (S)-6 with 75% ee.

Crystal structures of the synthetic intermediate 3-[(6-chloro-7H-purin-7-yl)methyl]cyclobutan-1-one, and of two oxetanocin derivatives: 3-[(6-chloro-8,9-dihydro-7H-purin-7-yl)methyl]cyclobutan-1-ol and 3-[(6-chloro-9H-purin-9-yl)methyl]cyclobutan-1-ol

The crystal structures of an intermediate, C10H9ClN4O, 3-[(6-chloro-7H-purin-7-yl)methyl]cyclobutan-1-one (I), and two N-7 and N-9 regioisomeric oxetanocin nucleoside analogs, C10H13ClN4O, 3-[(6-chloro-8,9-dihydro-7H-purin-7-yl)methyl]cyclobutan-1-ol (II) and C10H11ClN4O, 3-[(6-chloro-9H-purin-9-yl)methyl]cyclobutan-1-ol (IV), are reported. The crystal structures of the nucleoside analogs confirmed the reduction of the N-7- and N-9-substituted cyclobutanones with LiAl(OtBu)3 to occur with facial selectivity, yielding cis-nucleosides analogs similar to those found in nature. Reduction of the purine ring of the N-7 cyclobutanone to a dihydropurine was observed for compound (II) but not for the purine ring of the N-9 cyclobutanone on formation of compound (IV). In the crystal of (I), molecules are linked by a weak Cl...O interaction, forming a 21 helix along [010]. The helices are linked by offset π–π interactions [intercentroid distance = 3.498 (1) Å], forming layers parallel to (101). In the crystal of (II), molecules are linked by pairs of O—H...N hydrogen bonds, forming inversion dimers with an R 2 2(8) ring motif. The dimers are linked by O—H...N hydrogen bonds, forming chains along [001], which in turn are linked by C—H...π and offset π–π interactions [intercentroid distance = 3.509 (1) Å], forming slabs parallel to the ac plane. In the crystal of (IV), molecules are linked by O—H...N hydrogen bonds, forming chains along [101]. The chains are linked by C—H...N and C—H...O hydrogen bonds and C—H...π and offset π–π interactions [intercentroid distance = 3.364 (1) Å], forming a supramolecular framework.

Origins of Contrasteric π-Facial Selectivity in Epoxidations of Encumbered Tetrahydropyridines by a Bifunctional Peracid

The origins of contrasteric diastereoselectivity in the epoxidation of encumbered tetrahydropyridines have been elucidated via density functional theory (DFT) calculations. A strong energetic preference for OH···N hydrogen bonding was found for epoxidation transition states of the unsubstituted tetrahydropyridine. For hexasubstituted tetrahydropyridines, the diastereofacial selectivity is dictated by both the strong OH···N hydrogen bonding and the conformational preference of the tetrahydropyridine substrate.

The Sato/Chida Synthesis of Paclitaxel (Taxol®)

Paclitaxel (Taxol®) 3 is widely used in the clinical treatment of a variety of cancers. Takaaki Sato and Noritaka Chida of Keio University envisioned (Org. Lett. 2015, 17, 2570, 2574) establishing the central eight-membered ring of 3 by the SmI2-mediated cyclization of 1 to 2. The starting point for the synthesis was the enantiomerically-pure enone 5, pre­pared from the carbohydrate precursor 4. Conjugate addition to 5 proceeded anti to the benzyloxy substituent to give, after trapping with formaldehyde and protection, the ketone 6. Reduction and protection followed by hydroboration led to 7, that was, after protection and deprotection, oxidized to 8. The second ring of 3 was added in the form of the alkenyl lithium derivative 9, prepared from the trisylhydrazone of the corresponding ketone. Hydroxyl-directed epoxidation of 10 proceeded with high facial selectivity, leading, after reduction and protection, to the cyclic carbonate 11. Allylic oxidation converted the alkene into the enone, while at the same time oxidizing the benzyl protecting group to the ben­zoate, to give 12. Reduction of the ketone 12 led to a mixture of diastereomers. In practice, only one of the diastereomers of 1 cyclized cleanly to 2, as illustrated, so the undesired diastereomer from the NaBH4 reduction was oxidized back to the enone for recycling. For convenience, only one of the diastereomers of 2 was carried forward. To establish the tetrasubstituted alkene of 3, the alkene of 2 was converted to the cis diol and on to the bis xanthate 13. Warming to 50°C led to the desired tet­rasubstituted alkene, sparing the oxygenation that is eventually required for 3. For convenience, to intercept 16, the intermediate in the Takahashi total synthesis, both xanthates were eliminated to give 14. Hydrogenation removed the disubsti­tuted alkene, and also deprotected the benzyl ether. Oxidation followed by Peterson alkene formation led to 15, that was carried on to the Takahashi intermediate 16 using the now-standard protocol for oxetane construction. It is a measure of the strength of the science of organic synthesis that Masahisa Nakada of Waseda University also reported (Chem. Eur. J. 2015, 21, 355) an elegant synthesis of 3 (not illustrated).

The Njardarson Synthesis of Vinigrol

The diterpene vinigrol 3, isolated from Virgaria nigra F-5408, is a tumor necrosis factor (TNF) inhibitor. Jon T. Njardarson of the University of Arizona envisioned (Angew. Chem. Int. Ed. 2013, 52, 8648) that Wharton fragmentation of 1 could deliver 2, suit­ably functionalized for elaboration to 3. The tetracyclic 1 was prepared by the triply-convergent assembly of the phenol 11. Addition of allyl magnesium bromide to 4 proceeded with high regio- and geomet­ric selectivity, to give an alcohol that was methylated, then iodinated with inversion to give 5. Condensation of the phosphonate 7 with the derived aldehyde 6 led to the alcohol 8, that was coupled under Mitsunobu conditions with the phenol 9 to give 10. Oxidation of 11 gave an intermediate that underwent intramolecular Diels–Alder cycloaddition to deliver 12. On exposure to the Pd catalyst, 12 cyclized to the diene 13. On exposure to tBuOK/ tBuOH, the mesylate 1 smoothly fragmented to the hoped-for ketone 2. Although this has been referred to as a Grob fragmentation, in fact this reaction was developed (J. Org. Chem. 1961, 26, 4781) by Peter S. Wharton, then at the University of Wisconsin, and would more properly bear his name. Subsequent transformations took advantage of the hindered nature of the trisubsti­tuted alkene of 2. Hydrogenation of the disubstituted alkene proceeded selectively, to give an intermediate that was condensed with 14, leading to the enone 15. Two more selective hydrogenations, with the Wittig methylenation in between, completed the construction of the pendant isopropyl group. Once the isopropyl group was installed, what remained was the oxidation of 16 to 19. The epoxidation of 17 proceeded with high facial selectivity, to give an intermedi­ate that was carried on by iodination and reduction to the alcohol 18. Allylic oxidation converted 18 into 19, that was deprotected to give Vinigrol 3. It is instructive to compare and contrast this approach to vinigrol 3 with the two that we have previously highlighted (OHL September 6, 2010; December 24, 2012). Each strategy offers its own advantages.