*2.6. Synthesis of 9'-CH2OH Lactones*

With **3** and **6** prepared, acid **6** was then converted to acid chloride **2** in situ using oxalyl chloride, before undergoing a TiCl4.2THF induced acyl-Claisen rearrangement [17,27] with (*E*)-allylic morpholine **3**. One equivalent of TiCl4.2THF was required, as we have previously shown acyl-Claisen rearrangements with aromatic substituents require stochiometric amounts of Lewis acid to occur [27]. The rearrangement successfully took place to give racemic morpholine amide **1** in 85% yield as a single *syn*-diastereomer. Dihydroxylation, again under Upjohn conditions, cyclised amide **1** in situ to γ-lactone **16** in 88% yield (Scheme 5). The cyclisation proceeds through a diol intermediate, from which anti-**17** spontaneously formed lactone **16**. *Syn*-diol **17** was also formed in 12% yield and did not undergo cyclisation. This allowed *syn*-**17** to be isolated and treated with 2 M HCl to give the

epimeric lactone **18** with a *trans*,*cis* relationship between the C-8, C-8' and C-9 stereocentres. Under both sets of conditions, the respective diastereomer (**16** or **18**) was afforded as the sole product. The benzyl ether in each diastereomer was deprotected to their respective phenol, in 56% yield as *trans*,*cis* isomer **19** and *trans*,*trans* isomer **20** in quantitative yields (Scheme 5).

**Scheme 5.** Acyl-Claisen rearrangement and cyclisation. Reagents and conditions: (**i**) TiCl4.2THF (1 equiv.), *i*-Pr2NEt (1.5 equiv.), CH2Cl2, rt, 24 h, **1** 85%; (**ii**) OsO4 (2.5 mol-%), NMO (3 equiv.), *t*-BuOH/H2O (1:1), rt, 4 days, *syn*-**17** 12%, **16** 88%; (**iii**) 2M HCl, MeOH, reflux, 4 h, **18** 94%; (**iv**) Pd/C (10% *w*/*w*), H2, EtOAc, rt, 19 h, **19** 56%. **20** quant.

#### *2.7. Synthesis of Lactone Derivatives*

With lactone **16** successfully synthesised, a range of C-9 functionalised derivatives were targeted to explore the effects of modifications at this position on the anti-proliferative activity.

#### 2.7.1. Ester Derivatives

A series of ester derivatives was completed to add prodrug-like groups, capable of being cleaved by cellular esterases [28]. Differing ester groups were installed using the addition of acid chlorides to lactone **16** with Et3N and catalytic DMAP. Differing chain lengths and aromaticity were accessed with the synthesis of acetate **21**, propionate **22**, and benzoate **23** esters (Scheme 6). An additional benzoate ester **24** was synthesised from isomer **19**, in 48% yield, to provide an example of the epimeric *trans*,*cis* form. Following derivatisation of the 9'-CH2OH functionality, the benzylic ether at C-4 was removed via catalytic hydrogenation to give the free phenol, a directly comparable analogue of arctigenin. The synthesis of **21**–**24** was achieved in yields ranging from 72–88%. Deprotection of the benzyl ether in all the ester analogues gave C-4 phenols **25**–**27**, in yields of 64% to quantitative (Scheme 6).

**Scheme 6.** Synthesis of esters. Reagents and conditions: (**i**) Et3N (2 equiv.), DMAP (5 mol-%), RCOCl (1.2 equiv.), CH2Cl2, 0 ◦C to rt, 4–23 h, **21**–**23** 72–88%; (**ii**) Pd/C (10% *w*/*w*), H2, EtOAc, rt, 22–24 h, **25**–**27** (64%–quant.); (**iii**) Et3N (2 equiv.), DMAP (5 mol-%), BzCl (1.2 equiv.), CH2Cl2, 0 ◦C–rt, 21 h, **24** 48%; (**iv**) Pd/C (10% *w*/*w*), H2, EtOAc, rt, 19 h, **28** quant.
