Table 1.
Optimization of HBD catalyst structure and reaction conditionsa
| ||||||||
|---|---|---|---|---|---|---|---|---|
| entry | HX (mol%) |
HBD (mol%) |
conversion (%)b |
yield (%)b |
d.r. 2ab | 2a : 3ab | ee 2a (%)c |
ee 3a (%)c |
| 1 | — | 4 (10) | n.r. | n.r. | — | — | — | — |
| 2 | HCl (8) | 4 (10) | 33 | 28 | 10 : 1 | 3.5 : 1 | 76 | 74 |
| 3 | MsOH (8) | 4 (10) | 100 | trace | — | — | — | — |
| 4 | TsOH H2O (8) | 4 (10) | 87 | 30 | 4 : 1 | — | 31 | — |
| 5 | BzOH (8) | 4 (10) | n.r. | n.r. | — | — | — | — |
| 6 | HOP(O)(OPh)2 (8) | 4 (10) | n.r. | n.r. | — | — | — | — |
| 7 | HCl (8) | 5 (10) | 41 | 32 | 22 : 1 | 6.5 : 1 | 89 | 77 |
| 8 | HCl (8) | 6a (10) | 45 | 44 | 23 : 1 | 4.4 : 1 | 96 | 95 |
| 9 | HCl (8) | 6b (10) | 34 | 32 | 49 : 1 | 3.0 : 1 | 98 | 98 |
| 10 | HCl (8) | 7 (10) | 35 | 25 | 12 : 1 | 2.4 : 1 | 87 | 89 |
| 11 | HCl (30) | 6b (10) | 96 | 94 | > 50 : 1 | 3.1 : 1 | 96 | 98 |
| 12 | HCl (30) | 6b (5) | 88 | 85 | 30 : 1 | 3.1 : 1 | 92 | 94 |
| 13 | AcCl + EtOH (30) | 6b (5) | 93 | 91 | 38 : 1 | 3.0 : 1 | 95 | 97 |
| 14d | AcCl + EtOH (30) | 6b (5) | — | 82 | 36 : 1 | — | 95 | — |
| ||||||||
a
Conducted using 0.08 mmol of 1a with Brønsted acid cocatalysts delivered as solutions in Et2O.
b
Determined from crude reaction mixtures using 1H NMR spectroscopy with mesitylene internal standard. Yield refers to the combined yield of products trans/cis 2a and 3a except for entry 14.
c
Determined by GC analysis using a chiral stationary phase. n.r. = no reaction.
d
Reaction was quenched by the addition of 60 mol% KHMDS.