The octahedral titanium(IV) complexes trans,mer-[Ti{R 3 N(CH 2 C 6 H 2 -2-O-4-R 2 -6-R 1 ) 2 } 2 ] (R 1 = Me, OMe, Cl; R 2 = Me, OMe, F, Cl; R 3 = Me, Et; not all combinations) are synthesised in two steps from simple phenols in 36-53 % overall yield. The highly crystalline (4 X-ray structures) complexes are active against MCF-7 (breast) and HCT-116 (colon) cancer cell lines showing widely varying GI 50 values in the range 1-100 μM depending on R 1 -R 3 . Highest activities are realised when R 1 = OMe and R 2 , R 3 = Me (GI 50 ca. 1 μM for MCF-7 and 2-3 μM for [a]
ReactIR
studies of mixtures of AlEt3 (A) and cyclohex-2-en-1-one
(CX) in Et2O indicate
immediate formation of the Lewis acid–base complex CX·A at −40 °C (K = 12.0 M–1, ΔG°react = −1.1 kcal
mol–1). Copper(I) catalysts, derived from precatalytic
Cu(OAc)2 (up to 5 mol %) and (R,S,S)-P(binaphtholate){N(CHMePh)2} (Feringa’s ligand (L), up to 5 mol %)
convert CX·A (0.04–0.3 M) into its 1,4-addition
product enolate (E) within 2000 s at −40 °C.
Kinetic studies (ReactIR and chiral GC) of CX·A, CX, and (R)-3-ethylcyclohexanone (P, the H+ quenching product of enolate E)
show that the true catalyst is formed in the first 300 s and this
subsequently provides P in 82% ee. This true catalyst
converts CX·A to E with the rate law
[Cu]1.5[L]0.66[CX·A]1 when [L]/[Cu] ≤ 3.5. Above this
ligand ratio inhibition by added ligand with order [L]−2.5 is observed. A rate-determining step (rds)
of Cu3
L
2(CX·A)2 stoichiometry is shown to be most consistent with the
rate law. The presence of the enolate in the active catalyst best
accounts for the reaction’s induction period and molecularity
as [E] ≡ [CX·A]. Catalysis proceeds
through a “shuttling mechanism” between two C
2 symmetry related ground state intermediates.
Each turnover consumes 1 equiv of CX·A, expels one
molecule of E, and forms the new Cu–Et bond needed
for the next cycle. The observed ligand (L) inhibition
and a nonlinear ligand L ee effect on the ee of P are well simulated by the kinetic model. DFT studies (ωB97X-D/SRSC)
support coordination of CX·A to the groundstate
Cu trimer and its rapid conversion to E.
Simple enantioselective synthesis of 6,6-disubstituted pentafulvenes bearing chiral pendant hydroxy groups are attained by cascade reactivity using commercially available proline-based organocatalysts. Condensation of cyclopentadiene with the acetyl function of a 1,2-formylacetophenone, followed by cyclization of a resulting fulvene-stabilized carbanion with the formyl group, generates bicyclic chiral alcohols with initial er values up to 94:6. Exceptional enantio-enrichment of the resultant alcohols results upon crystallization-even near racemic samples spontaneously de-racemize. This enables new families of substituted cyclopentadienes that are both enantiomerically and diastereomerically pure to be rapidly attained.
Combination of [Cu(MeCN)4]TFA•TFAH (TFA = O2CCF3) with Feringa's phosphoramidite ligand (L A ) provides an exceptionally active (0.75 mol%) catalyst for asymmetric conjugate additions of ZnR2 (R = Et, Me at -40 to -80 o C) to enones. Kinetic and other studies of the addition of ZnEt2 to cyclohex-2-en-1-one indicate a transition state stoichiometry composition: (ZnEt2)3(enone)4Cu2(L A )3 that is generated by transmetalation from Et2Zn(enone)2. Catalyst genesis is significantly slower than turnover (which has limited previous attempts to attain useful kinetic data); in the initial stages varying populations of catalytically inactive, off-cycle, species are present. These issues are overcome by a double-dosing kinetic analysis protocol. A rest state of [L A Cu(Et)(µ-TFA)(µ-{(enone)(ZnEt)2(enolate)})CuL A2 ] + (through the equivalence of enolate = enone + ZnEt2) is Manuscript for Organometallics, Woodward and co-workers Page 2 of 19supported by DFT studies (ωB97X-D/SRSC). Rate determining ZnEt2(enone)2 transmetalation drives the exceptionally high catalytic activity of this system.
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