Asymmetric Induction of Conduritols via AAA Reactions: Synthesis of the Aminocyclohexitol of Hygromycin A

Abstract

Two synthetic routes towards the construction of the aminocyclohexitol moiety of hygromycin A have been developed based on palladium-catalyzed asymmetric alkylation of conduritol derivatives. A protocol has been established whereby this biologically relevant molecule is formed from benzoquinone. A conduritol A derivative is synthesized in eight steps from benzoquinone and is then subjected to the palladium reaction. From this flexible intermediate, four epimers of the aminocyclitol, including the natural one, can be obtained with complete stereoselectivity. Racemic conduritol B derivatives are available in four steps from benzoquinone, and these are then made enantiomerically pure by a palladium-catalyzed dynamic kinetic resolution. From the chiral conduritol B, the aminocyclitol is available in six steps. Excellent levels of enantio- and diastereoselectivity highlight these strategies.

Direct enantio-convergent transformation of racemic substrates without racemization or symmetrization

“…There are no efficient ways to racemize such tertiary ethers, indicating DKR is not applicable. Although DYKAT of some racemic allylic esters have been reported in transition-metal-catalyzed asymmetric allylic alkylation, 10,11,[13][14][15][16][17][18] successful cases are limited to the acyclic allylic esters or cyclic ones bearing symmetrical substituents about the allylic system or bearing an electron withdrawing group. Such structures enable DYKAT by racemization through isomerization 10,11,15,16 or symmetrization via the formation of pseudo-meso allylmetal complexes.…”

“…This indicates that this reaction does not include a pseudo-meso π allylmetal intermediate which is observed in other transition-metal-catalyzed DYKAT processes (entry 8). 9,10,16,17 Either enantio-enriched forms of the starting material, (S)-1b (93% ee) or (R)-1b (94% ee) were also converted into the same enantiomer, (S)-4b (entries 9 and 10); the reaction of (S)-1b resulted in a higher ee (99% ee) than that obtained from (rac)-1b, and the reaction of (R)-1b gave a lower ee (85% ee). The stereochemical outcomes indicate that the reactions of (S)-1b and (R)-1b proceed via two distinct pathways, anti-S N 2' with higher enantioselectivity and the syn-S N 2' pathway with slightly lower enantioselectivity, respectively.…”

“…Such structures enable DYKAT by racemization through isomerization 10,11,15,16 or symmetrization via the formation of pseudo-meso allylmetal complexes. 10,11,17,18 The reaction of (rac)-1a was first carried out with bis(pinacolato)diboron 3 (1.5 equiv.) in the presence of 5 mol % of Cu(O-t-Bu) and a chiral phosphine ligand [(R,R)-QuinoxP* (2a)] 27 in diethyl ether at 30 °C (Table 1).…”

“…To overcome the limitation caused by this incomplete conversion, many elegant deracemization processes have been designed that can transform both enantiomers of the racemic starting materials into a single enantiomer of the product. Dynamic kinetic resolution (DKR) [7][8][9] and dynamic kinetic asymmetric transformation (DYKAT) [10][11][12][13][14][15][16][17][18] are representative examples (Figures 1b and 1c). Dynamic kinetic resolution can be achieved by combining an enantioselective reaction with the rapid racemization of the starting materials ( Figure 1b).…”

Stereospecific synthesis of N-tosyl derivatives of dihydroconduramine E-2 and ent-F-2

“…34,35 (3aR,7aS)-2,2-Dimethyl-3-tosyl-2,3,3a,6,7,7a-hexa-hydrobenzo[d]oxazole (21). A mixture of carbamate 15 (2 g, 6.83 mmol) and potassium carbonate (1.7 g, 12.3 mmol) in methanol/ water (47:3 mL) was stirred at room temperature for 18 h, when TLC (silica gel, 80% ethyl acetate/hexane) indicated complete reaction.…”