Table 1.

Optimization of the asymmetric addition of ynamides to isatins.^a

Entry	R	Catalyst	Ligand	Conditions	Yield (%)b	Ee (%)d
1	Me	Zn(OTf)2	L1	C6H6, DIPEA, 25 °C	99	<1
2	Me	Zn(OTf)2	L2	DCE, DIPEA, 25 °C	86	<1
3	Me	Zn(OTf)2	L3	DCE, DIPEA, 25 °C	94	2
4	Me	Zn(OTf)2	L4	DCE, DIPEA, 25 °C	89	1
5	Me	CuI	L3	DCM, DIPEA, 25 °C	64	16
6	Me	CuI	L4	DCM, DIPEA, 25 °C	51	17
7	Me	/	L5	DCE, DIPEA, 25 °C	54	4
8	Me	(CuOTf)2·Tol	L6	CHCl3, 25 °C	99 c	79
9	Me	(CuOTf)2·Tol	L4	CHCl3, 25 °C	<5 c	n.d.
10	Me	CuI	L6	CHCl3, 25 °C	<50 c	80
11	Me	CuI	L3	CHCl3, 25 °C	<50 c	9
12	Me	Zn(OTf)2	L6	CHCl3, 25 °C	<5 c	n.d.
13	Me	/	/	CHCl3, DIPEA, 25 °C	n.r.	n.d.
14	Me	(CuOTf)2·Tol	/	CHCl3, DIPEA, 25 °C	n.r.	n.d.
15	Ph	(CuOTf)2·Tol	L6	CHCl3, Et3N, 50 °C	27	2
16	Me	(CuOTf)2·Tol	L6	CHCl3, 0 °C	93	90
17	Ph	(CuOTf)2·Tol	L6	CH2Cl2, 0 °C	97	90
18	Ph	(CuOTf)2·Tol	L6	THF, 0 °C	36	96
19	Ph	(CuOTf)2·Tol	L6	Et2O, 0 °C	42	68
20	Ph	(CuOTf)2·Tol	L6	MTBE, 0 °C	61	66
21	Ph	(CuOTf)2·Tol	L6	CHCl3, 0 °C	99	98
22	Ph	(CuOTf)2·Tol	L7	CHCl3, 0 °C	98	85
23	Ph	(CuOTf)2·Tol	L8	CHCl3, 0 °C	99	91
24	Ph	(CuOTf)2·Tol	L9	CHCl3, 0 °C	93	90

^[a]Reaction Conditions: Ynamide (0.3 mmol, 1.5 equiv.), isatin (0.2 mmol, 1 equiv.), catalyst (5 mol%), ligand (15 mol%), base (1.1 equiv.) in 0.1 mL of solvent.

^[b]Isolated yield.

^[c]Conversion determined by HPLC.

^[d]Ee determined by chiral HPLC on a Phenomenex Lux 5μ Cellulose-3 column (mobile phase = 85:15 hexanes-EtOH, flow rate = 1.0 mL/min, λ = 254 nm), n.r. = no reaction, n.d. = not determined.