Stereoselective Formation of cis-Trisubstituted 1,3-Dioxanes

Oxa-Michael-based divergent synthesis of artificial glutamate analogs

“…2B. Both conguration and conformation of 11r are identical to those we observed recently in the simple case (3 / 4, see Scheme 1), 16 showing that the 1,3-dioxane formation in this study is also thermodynamically controlled (see below for the mechanism).…”

“…Since the second conjugate addition is generally a thermodynamically controlled, reversible process, production of more stable (7R*) isomer 11r predominated over the (7S*) epimer 11s, as discussed also in our preliminary study. 16 It should be also noted here that, in that preliminary study employing a simple substrate, the (7S) epimer had not been obtained. 16 Generation of the less stable (7S*) epimer 11s in this study would be due to unfavorable steric interactions between the acetyl group and the benzyl ester on the near side in 11r (Scheme 4B), that make the energy difference between the two diastereomers (11r and 11s) smaller.…”

“…16 It should be also noted here that, in that preliminary study employing a simple substrate, the (7S) epimer had not been obtained. 16 Generation of the less stable (7S*) epimer 11s in this study would be due to unfavorable steric interactions between the acetyl group and the benzyl ester on the near side in 11r (Scheme 4B), that make the energy difference between the two diastereomers (11r and 11s) smaller. Then two benzyl groups of 11r were removed by hydrogenolysis 21 to cleanly provide glutamate analog 1ar ((2R*,7R*)-TKM-50) in 86% yield (Scheme 3).…”

“…3) could even be reasonably explained, supporting the origin of the stereoselectivity we proposed in Scheme 4. 16 It is of interest to note that the formed skeleton changes signicantly, just by interchanging the order of the oxa-Michael reaction and the hemiacetalization (see Schemes 4 and 6). Therefore, it is expected that our methodology is generally of use for discovery of biologically active small molecules.…”

“…The alkene 7 was subjected to cross metathesis with methyl vinyl ketone ( 8 ) mediated by Hoveyda-Grubbs second generation catalyst ( 9 ) 19 to provide enone 10 in 82% yield (Scheme 3). Upon exposure to paraformaldehyde as an equivalent of formaldehyde and 1,3,5-trioxane 16 in the presence of MsOH, 1,3-dioxane ring formed smoothly by oxa-Michael reaction to give rise to desired (7 R *)-heterotricycle 11r and the (7 S *) epimer 11s (structure not shown) in the ratio of >9 : 1, as well as the N -hydroxymethylated product 12r (see Scheme 3) and the (7 S *) epimer 12s (structure not shown). Since we had found that alkaline hydrolysis is of use to remove the N -hydroxymethyl group, the mixture of hemiaminals ( 12r / 12s ) and free amides ( 11r / 11s ) was treated with ammonium hydroxide 20 to obtain free amide 11r in 73% isolated yield (2 steps), and free amide 11s in 10% yield (estimated by NMR, 2 steps).…”