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After the 4-step substrate synthesis of crotylated 1,6-enyne (161) with the E/Z isomer in 3 to 1 ratio, the optimization of gold(I) mediated divergent synthesis began with the catalyst screening and is summarized in Table 3. By treatment of in situ prepared cationic gold(I) complex Ph3PAu(BF4) in DCM, the spirooxindole (165) was formed in 33% yield (entry 1).

With 5 mol% of AuCl₃ as the gold(III) catalyst, the cycloisomerization reaction provided the ring expansion product quinolone (166) in 23% yield, which did not improve with doubling the catalyst loading and resulted in complex product mixtures (entry 2-3). When the gold(I) catalyst with NHC as ligand (I) was applied for the transformation, the mixture of spirooxindole (165) and quinolone (166) was isolated as products in 43% and 7 % yield,

43 respectively (entry 4). Delightfully, the quinolone (166) could be selectively generated by utilizing the bulky phosphine as gold(I) ligand (II) in good yield. Fine tuning the steric factor of phosphine ligand revealed that the biphenyl ring of phosphine bearing 1,3,5-tri-iso-propyl groups (IIa) provided the highest yield of 67% as compared to others bulky phosphine ligands (entry 5-7). Interestingly, the epimer of quinolone (epi-166) was also isolated in the cat IIa catalyzed reaction in 20% yield, which would be the product from the Z-1,6-enyne (Z-161). Treatment of more electrophilic gold(I) catalyst with phosphite ligand (III) selectively gave the spirooxindole as the product in satisfactory yield (entry 8). The Z-1,6-enyne (Z-161) seemed to be inert in this catalytic condition, which was in 10%

recovery.

In the initial catalyst screening, two structurally distinct scaffolds, spirooxindole (165) and quinolone (166), were generated in a selective manner by bulky phosphine and electrophilic gold(I) catalysts, (IIa and III), respectively; and the screening of solvent and catalyst loading were followed up for the further improvements. However, no further improvement was observed during the whole process. For the bulky phosphine gold(I) catalyzed spirooxindole formation (IIa), the non-selective result was observed while using toluene as the solvent (entry 9). As the polar solvent, both of ACN and DMF diminished the power of catalysts to give the starting material recovery as the outcome (entry 10, 11) THF, as the optimal solvent for the df-oxindole formation, turned out to be incompatible in the condition and leading to the polymerization of THF (entry 12). When decreasing the catalyst loading from 5 mol% to 3 mol%, the yield of spirooxindole also dropped to 27%. On the other hand, by using toluene as solvent, the phosphite gold(I) catalyzed quinolone formation (III) could deliver the desired product thought in moderate yield (entry 14). When swiching the solvent to ACN or DMF, stating material was recovered due to the deactivation of catalyst by the polar solvent (entry 15 and 16). The THF was also proven to be not compatible as solvent to the gold(I) catalyzed condition that leading to the polymerization (entry 17). Reducing the catalyst loading to 3 mol% slightly decreased the yield of the quinolone formation (entry 18).

44 Table 3. Reaction optimization for gold(I) catalyzed divergent scaffold synthesis (I).

Entry [Au] (5 mol%) Solvent Yield (%)

165 166 epi-166

1 Ph₃PAu(BF₄) DCM 33 - -

2 AuCl3 DCM - 23 -

3 AuCl3 DCM -^[a]

4^[b] I DCM 43 7 -

5 II DCM - 57 -

6 IIa DCM - 67 20

7 IIb DCM - 43 -

8^[c] III DCM 60 - -

9 IIa toluene -^[a]

10 IIa ACN -^[d]

11 IIa DMF -^[d]

12 IIa THF -^[e]

13^[d] IIa DCM - 27 -

14 III toluene 40 - -

15 III ACN -^[d]

16 III DMF -^[d]

17 III THF -^[e]

18^[f] III DCM 58 - -

[a] Non-selective reaction. ^[b] Starting material was in 26% recovery. ^[c] Z-161 was in 10%

recovery. ^[d] Starting material recovery. ^[e] THF polymerized. ^[f] Catalyst loading: 3 mol%.

45 After identification of the optimal conditions for the formation of spirooxindoles (165, Table 3, entry 8) and quinolones (166, Table 3, entry 6), I envisioned that the cyclopropane moiety of the gold carbene intermediate could be opened up by nucleophilic addition, allowing the formation of df-oxindoles via O-migration, as shown in Table 4. In the presence of gold(I) catalyst (II), 20 equivalents (eq.) of MeOH were used as the nucleophile to trap the gold carbene intermediate. Since no reaction proceeded at room temperature, the reaction temperature was raised to 60 ^oC that also required switching the solvent from DCM to DCE.

Indeed, he df-oxindole (167) was isolated in 62% yield, accompanied by the Mayer-Schuster rearrangement (M.-S. rear.) product (136) in 19% yield (entry 1-2). The replacement of catalyst from phosphine gold(I) catalyst (II) to NHC gold(I) catalyst (I) or phosphite gold(I) catalyst (III) didn’t provide a better yield of 167 (entry 3, or 4). After tuning the electronic property of the cationic gold(I) catalyst, the role of steric nature of the catalyst on reaction was investigated by tuning the bulky groups on the JohnPhos ligand, such as tBu to Ad or unsubstituted phenyl group to 1,3,5-tri-iso-propyl phenyl group. However, none of them gave higher yield than the initial trial (entry 5, 6).

We assumeed that the exccess amount of MeOH influenced the formation of the M.-S.

rearrangement product (136). Therefore, a series of reactions were set to see the effect of the amount of MeOH on the reaction outcome (entry 7-10). Decreasing the amount of MeOH led to corresponding decrease in the formation of 136. With only 1.0 eq. of MeOH, no more 136 was formed. At the same time, the quinolone (166) started to form when the 3.0 eq or less MeOH was used. With 5 mol% of II in the presence of 10 eq. of MeOH, the reaction afforded the df-oxindole (4a) in 73% yield (entry 7). Lowering the catalyst loading to 3 mol% also decreased the product yield (entries 11). The nucleophiles other than MeOH were also investigated, such as H₂O, AcOH, and indole. In the case of H₂O, a heterogeneous mixture was formed affording a mixture of 166, epi-166, and hydroxyl adduct 167OH in 30%, 15%, and 23% yield, respectively (entry 12). The AcOH nucleophile gave the diasteromeric mixture of acetyl adduct 167OAc in 56% yield (entry 13). However, the indole molecule failed to serve as carbon nucleophile and did not form the expected adduct (entry 14).^[55]

46 Table 4. Reaction optimization for gold(I) catalyzed divergent scaffold synthesis (II).

[a] Reaction was operated at rt. ^[b] Starting material recovery. ^[c] Catalyst loading: 3 mol%.

Entry [Au] Solvent Nu (eq) Yield (%)

167 166 epi-166 136

1^[a] II DCM MeOH (20.0) no reaction

2 II DCE MeOH (20.0) 62 - - 19

3 I DCE MeOH (20.0) 27 - - 34

4 III DCE MeOH (20.0) 20 - - -

5 IIa DCE MeOH (20.0) 56 - - -

6 IIb DCE MeOH (20.0) 50 - - -

7 II DCE MeOH (10.0) 73 - - 18

8 II DCE MeOH (3.0) 56 11 - 7

9 II DCE MeOH (1.0) 43 32 - -

10 II DCE MeOH (0.5) 30 24 - -

11^[c] II DCE MeOH (10.0) 64 - - -

12 II DCE H2O (20.0) 23 (167OH) 30 15 -

13 II DCE AcOH (20.0) 56 (167OAc) 20 13 -

14 II DCE indole (2.0) - 37 - 23

47 3.3.2 Reaction scope

The extensive reaction screening and optimization identified suitable conditions to selectively form spirooxinodle (165), quinolone (166), and df-oxindole (167), in satisfactory yield by merely changing the ligand of the gold(I) catalyst and applying the nucleophile to the reaction (Scheme 22). Based on these optimal conditions, I started to investigate the functional group tolerance for the diverse scaffold generating transformations. As I had already observed that the variation in the allyl moiety alters the scaffold formation, functional group variation was performed at the phenyl ring, aryl ring of the oxindole, and substituents on nitrogen for each scaffold generating gold(I) catalyzed reaction.