•Three different synthetic routes to 2-silyl substituted 1,3-dienes are presented.•Hydrosilylation of enynes yields mixtures of regioisomers.•Grignard chemistry is the best synthetic route when 2-halo-1,3-dienes are available.A number of 2-silicon substituted 1,3-dienes have been prepared by one of three routes: 1) Reactions of 1,3-dienyl Grignard reagents with silyl electrophiles or silyl Grignard reagents with 1,3-dienyl electrophiles; 2) Hydrosilylation of enynes; 3) Enyne cross metathesis. The strengths and limitations of each preparative method are discussed.A number of 1,3-dienes have been prepared by: 1) Reactions of 1,3-dienyl Grignard reagents with silyl electrophiles or silyl Grignard reagents with 1,3-dienyl electrophiles; 2) Hydrosilylation of enynes; or 3) Enyne cross metathesis. Use of Grignard chemistry where possible is preferred over enyne hydrosilyation or cross metathesis.

This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5 years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, that is, inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.

The phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway is constitutively activated in a substantial proportion of prostate tumors and is considered a key mechanism supporting progression toward an androgen-independent status, for which no effective therapy is available. Therefore, PI3K inhibitors, alone or in combination with other cytotoxic drugs, could potentially be used to treat cancer with a constitutive activated PI3K/Akt pathway. To selectively target advanced prostate tumors with a constitutive activated PI3K/Akt pathway, a prostate cancer-specific PI3K inhibitor was generated by coupling the chemically modified form of the quercetin analogue LY294002 (HO-CH2-LY294002, compound 8) with the peptide Mu-LEHSSKLQL, in which the internal sequence HSSKLQ is a substrate for the prostate-specific antigen (PSA) protease. The result is a water-soluble and latent PI3K inhibitor prodrug (compound 11), its activation being dependent on PSA cleavage. Once activated, the L-O-CH2-LY294002 (compound 10) can specifically inhibit PI3K in PSA-secreting prostate cancer cells and induce apoptosis with a potency comparable to that of the original LY294002 compound.

Several new 2-boron substituted dienes have been prepared and characterized. Their reactivity in Diels–Alder reactions has been examined and the boron substituted cycloadducts of those cycloaddition reactions have been used in cross coupling reactions. One-pot tandem Diels–Alder/cross coupling reactions of 2-boron substituted dienes are then also reported along with some experimental evidence that these one-pot reactions are proceeding through a Pd(II)-catalyzed Diels–Alder/cross coupling reaction pathway.

A number of alkynols have been prepared by Sonogashira coupling of propargyl alcohol to aromatic halides. Chelation-controlled addition of organometallic nucleophiles to these alkynols was then effected followed by the addition of the sulfur electrophiles, sulfur dioxide or thionyl chloride. This methodology was used to prepare a number of oxathiolene oxides, which have been screened as NQO1 (quinone oxidoreductase) inducers.A number of alkynols have been prepared by Sonogashira coupling of propargyl alcohol to aromatic halides. Chelation-controlled addition of organometallic nucleophiles to these alkynols was then effected followed by the addition of the sulfur electrophiles, sulfur dioxide or thionyl chloride. This methodology was used to prepare a number of oxathiolene oxides, which have been screened as NQO1 (quinone oxidoreductase) inducers.