When the first titanium complex with anticancer activity was identified in the 1970s, it was attractive, based on the presence of the dichloride unit in TiCl 2 Cp 2 (Cp = η-C 5 H 5 ) 2 , to assume its mode of biological action was closely aligned with cisplatin [cis-PtCl 2 (NH 3 ) 2 ]. Over the intervening 40 years however a far more complicated picture has arisen indicating multiple cellular mechanisms of cellular action can be triggered by titanium anti-cancer agents. This tutorial review aims to unpick the historical data and provide new researchers, without an explicit cancer biology background, a contemporary interpretation of both older and newer literature and to review the best techniques for attaining the identities of the biologically active titanium species and how these interact with the cancer cellular machinery. Key learning points(1) Understanding the problems in defining 'modes of action' in order to effectively design small molecular titanium-based therapeutic, agents when moving beyond simple 'structure vs. activity' correlations. (2) The dangers of over generalisation in historical 'mode of action' proposals in the absence of rigorous control experiments leading to proposals not fully in line with all (especially later) observations. (3) Titanium induced cellular morphology changes and contemporary thoughts on mode(s) of actionpresented in a way chemical scientists can 'get to grips with them' -understanding the hall marks of cellular death modes induced by titanium anti-cancer agents. (4) Modern tools for probing Ti-drug mechanisms of action, including: chiral probe complexes, added external proteins (transferrin, serum albumin); titanium solution speciation, and an overview of contemporary chemical-biology techniques of relevance to discovery of 'modes/mechanisms of action'.

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The copper‐catalysed (10 mol‐% CuBr·SMe2, CuCN·LiCl or CuI/PPh3) addition of RMgBr to the pentafulvene 1‐(cyclopenta‐2,4‐dien‐1‐ylidenemethyl)‐2‐methoxybenzene allows the formation of cyclopentadienyl derivatives with α‐CHR(2‐MeOPh) sidechains (R = Me, Et, nBu, iBu, allyl, Ph) without H– transfer. The deprotonation of these sec‐alkyl‐substituted cyclopentadienyls followed by the addition of TiCl4 allows the isolation of TiCl2{η5‐C5H4CHR(2‐OMePh)} as rac/meso mixtures that show activity against human colon, breast and pancreatic cell lines (GI50 2.3–42.4 μM).

Abstract:Unprecedented asymmetric copper-catalysed addition of ZnEt2 (ZnBu2) the (S,S) isomer is twice as active towards pancreatic, breast and colon cancer cell lines as its (R,R) enantiomer at 24 h.Asymmetric copper-catalysed 1,4-additions of organozincs, especially ZnEt2, to enones (e.g. ArCH=CHAc) have become commonplace in the last 10 years (Scheme 1a). [1] Although they contain an equally powerful anion accepting group (C5H4), equivalent copper-catalysed enantioselective carbocupration of pentafulvenes 1 is unknown (Scheme 1b). Such methodology could, if realised, provide rapid access to enantio-enriched substituted cyclopentadienyl ligands 2 having many applications in synthesis, catalysis [2] and biology. [3] To give just one specific example, the micromolar active anti-cancer titanocene dichloride 3 (presently known only as a mixture of stereoisomers) [3] would become available as single enantiomers, facilitating biological screening and potentially access to clinical trial candidates in time.Scheme 1. Exemplary common Cu(I)-catalysed asymmetric 1,4-addition vs. unknown carbozination and applications.

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.