Recent advances in the synthesis of fluorinated nucleosides

In an attempt to develop biologically active compounds from the inactive trans isomer (3a) of stilbene 1a, after asymmetric dihydroxylation to optically pure (R,R)-diol 8 the unexpected racemic diphenylacetaldehyde (9) was generated via a Pinacol rearrangement. Several derivatives of diphenylacetaldehyde 9 were synthesized (11-15) and reported. Further reaction of aldehyde 9 during desilylation through autoxidative decarbonylation afforded benzophenone 2b, designated hydroxyphenstatin, a potent antitumor and antimitotic agent. Hydroxyphenstatin showed potent inhibition of the tubulin assembly (IC(50) 0.82 microM) and exhibited an ED(50) of 2.5 microg/mL against the P388 lymphocytic leukemia cell line.

A pinacol rearrangement/oxidation synthetic route to hydroxyphenstatin.

The substituted fluorenyl cation, 9-(diphenylmethyl)fluoren-9-yl cation (4), is formed under stable ion conditions (low temperature/strong acid) from its corresponding alcohol 3. This ion is transformed to a substituted diphenyl methyl cation 8 at ambient temperature via an apparent 1,2-hydrogen shift. Irradiation of 9-(diphenylmethyl)fluoren-9-ol in methanol gives products derived from the corresponding cation along with radical-derived products from C-C and C-O homolysis processes. The laser flash photolysis of this alcohol gave a transient corresponding to cation 4. All of the photoproducts are derived from cation 4 or radical pathways. High level MO calculations point to a high barrier (23.8 kcal x mol(-1)) for the 1,2-hydride shift. This barrier is the consequence of the minimum energy conformation of this fluorenyl cation which is less than ideal for the periplanar geometry necessary for this process.

Studies of 9-fluorenyl carbocations. intramolecular hydride migration in a substituted 9-fluorenyl carbocation.

The first elimination reactions of silyl enol ethers to lithiated allenes are reported. These reactions allow a direct transformation of readily available silyl enol ethers into functionalized allenes. The action of three to four equivalents of lithium diisopropylamide (LDA) on silyl enol ethers results in the formation of lithiated allenes by initial allylic lithiation, subsequent elimination of a lithium silanolate, and finally, lithiation of the allene thus formed. Starting with amide-derived silyl imino ethers, lithiated ketenimines are obtained. A variety of reactions of the lithiated allenes with electrophiles (chlorosilanes, trimethylchlorostannane, dimethyl sulfate and ethanol) were carried out. Elimination of silanolate is observed only for substrates that contain the hindered SiMe2tBu or Si(iPr)3 moiety, but not for the SiMe3 group. The reaction of 1,1-dilithio-3,3-diphenylallene with ketones provides a convenient access to novel 1,1-di(hydroxymethyl)allenes which undergo a domino Nazarov–Friedel–Crafts reaction upon treatment with p-toluenesulfonic acid.



Die unseres Wissens ersten Eliminierungsreaktionen von Silylenolethern ermoglichen eine direkte Umwandlung leicht zuganglicher Silylenolether in Allene. Dabei werden die Substrate zunachst mit 3 bis 4 Aquivalenten Diisopropylamid (LDA) umgesetzt, wobei dilithiierte Allene gebildet werden. Diese Reaktion verlauft vermutlich uber allylische Lithiierung der Silylenolether, Eliminierung von Lithiumsilanolat und anschliesende Lithiierung des gebildeten Allen-Intermediats. Die Deprotonierung von Silyliminoethern, die bequem ausgehend von Amiden hergestellt werden konnen, liefert lithiierte Ketenimine. Die hergestellten lithiierten Allene wurden mit einer Reihe unterschiedlicher Elektrophile (Chlorsilane, Trimethylchlorstannan, Dimethylsulfat und Ethanol) umgesetzt. Eine Eliminierung von Lithiumsilanolat und die Bildung von Allenen wurde ausschlieslich fur Silylenolether beobachtet, die sterisch gehinderte Silylgruppen (SiMe2tBu oder Si(iPr)3) tragen, nicht dagegen fur Trimethylsilylenolether. Die Umsetzung von 1,1-Dilithio-3,3-diphenylallen mit Ketonen ermoglicht eine einfache und effiziente Darstellung von 1,1-Di(hydroxymethyl)allenen, die bei Behandlung mit p-Toluolsulfonsaure eine neuartige Domino Nazarov–Friedel–Crafts Reaktion eingehen.

Direct transformation of silyl enol ethers into functionalized allenes.

https://epublications.marquette.edu/cgi/viewcontent.cgi?article=1628&context=chem_fac

Hexabenzo[4.4.4]propellane: a helical molecular platform for the construction of electroactive materials.

Irradiation of 9,9‘-bifluorene-9,9‘-diol (1) gave 9-fluorenone and spiro[9H-fluorene-9,9‘(10‘-H)-phenanthren]-10‘-one (4), the latter arising from a pinacol rearrangement. The distribution of fluorenone and ketone 4 was solvent dependent with the latter being the major product in trifluoroethanol, a solvent known to stabilize carbocation intermediates. Laser flash photolysis of diol 1 in 2,2,2-trifluoroethanol or hexafluoro-2-propanol showed two transients absorbing at 350 and 505 nm with a weak band at 700 nm. The latter two peaks are assigned to the corresponding substituted 9-fluorenyl cation (5) formed from photoheterolysis of diol 1. Comparison of the decay kinetics between cation 5 and other 9-fluorenyl cations, the parent 9-fluorenyl and 9-phenyl-9-fluorenyl cations, showed that the decay of 5 was relatively insensitive to the nature of the solvent as compared to the latter two carbocations suggesting that unimolecular rearrangement in 5 competes with nucleophilic quenching.

Photochemical Pinacol Rearrangement

Synthesis of fluorocyclobutanones and their use in the synthesis of fluoronucleosides

An unusual fluoroketene reaction product

Fluorocyclobutanones can be prepared from reaction of hydroxycyclobutanones with diethylaminosulfur trifluoride (DAST). Other fluorine containing cyclobutanones can be prepared by alkene/fluoroketene cycloadditions. The photochemical ring-opening of these synthetic intermediates with 6-chloropurine produces fluorinated nucleoside analogs.

Synthesis of Fluorocyclobutanones and Their Use in the Synthesis of Fluoronucleosides.

The reaction of fluoroketene generated by the addition of triethylamine to a solution of 1,3-cyclohexadiene and fluoroacetyl chloride gave the expected [2 + 2] cycloaddition product. However, when the addition was reversed, an unexpected adduct arising from the reaction of four equivalents of fluoroketene with one equivalent of 1,3-cyclohexadiene was produced.

Hedieh Ghazi

Papers

Photochemical Pinacol Rearrangement

Synthesis of fluorocyclobutanones and their use in the synthesis of fluoronucleosides

An unusual fluoroketene reaction product

Synthesis of Fluorocyclobutanones and Their Use in the Synthesis of Fluoronucleosides.

An Unusual Fluoroketene Reaction Product.