Table 3.
Scope of the Michael/Henry/Ketalization Sequence To Form Tetrahydropyrans
| 6a | R1 | R2 | R3 | R4 | timeb (d) | yieldc (%) | drd | eee (%) |
|---|---|---|---|---|---|---|---|---|
| a | Me | Me | Ph | Ph | 5.5 | 79 | >20:1 | >99 |
| b | Me | Me | 2-BrC6H4 | Ph | 5.5 | 65 | 13:1 | 93 (99) |
| c | Me | Me | 3-MeOC6H4 | Ph | 6.5 | 45 | 6:1 | 97 (99) |
| d | Me | Me | 3,4–OCHH2OC6H3 | Ph | 5 | 27 | 2:1 | 95 (99) |
| e | Me | Me | 3-(N-Boc-indolyl) | Ph | 6 | 38 | 8:1 | 95 |
| f | Me | Me | 4-NO2C6H4 | Ph | 9 | 46 | 2:1 | 93 |
| g | Me | Me | Ph | 3-FC6H4 | 5.5 | 67 | 5:1 | 94 (99) |
| h | Me | Me | Ph | 4-MeC6H4 | 5.5 | 61 | 7:1 | 97 |
| i | Me | Me | Ph | 2-MeOC6H4 | 5.5 | 80 | 3:1 | 95 (99) |
| j | Me | Me | Ph | cyclopentyl | 5.5 | 68 | 4:1 | 96 |
| k | OMe | Me | Ph | Ph | 5.5 | 60 | 4:1 | 97 (99) |
| l | OMe | Et | Ph | Ph | 5 | 69 | 3:1 | 96 (99) |
| m | OtBu | Me | Ph | Ph | 9 | 34 | 2:1 | 98 |
a
The reaction was performed on a 0.4 mmol scale (0.5 M in DCM).
b
Sum of reaction time.
c
Combined yield of isolated product as a mixture of diastereomers after flash chromatography.
d
Diastereomeric ratio: major-(2S,3S,4S,5R,6R) vs minor-(2S,3S,4S,5S,6S) diastereomer determined by 1H NMR; after one recrystallization dr > 20:1.
e
Determined by HPLC analysis on a chiral stationary phase for the major diastereomer; value in parentheses after one recrystallization.