Formaldehyde as Tethering Organocatalyst: Highly Diastereoselective Hydroaminations of Allylic Amines.

Catalysts possessing sufficient activity to achieve intermolecular alkene hydroaminations under mild conditions are rare, and this likely accounts for the scarcity of asymmetric variants of this reaction. Herein, highly diastereoselective hydroaminations of allylic amines utilizing hydroxylamines as reagents and formaldehyde as catalyst are reported. This catalyst induces temporary intramolecularity, which results in high rate accelerations, and high diastereocontrol with either chiral allylic amines or chiral hydroxylamines. The reaction scope includes internal alkenes. Overall this work provides a new, stereocontrolled route to form complex vicinal diamines.

Total synthesis of muamvatin.

Enantioselective total synthesis of muamvatin was achieved by ring-chain tautomerization of an acyclic derivative assembled by sequential substrate-controlled stereoselective aldol reactions of a chiral ketone with two achiral aldehydes. Although the trioxaadamantane tautomer was shown to be thermodynamically more stable than alternative forms, the kinetic barrier to cyclization was significant. This observation raises doubts about the proposed formation of muamvatin as an artifact of isolation.

Rational design of aldol reactions that proceed via kinetic resolution with switchable enantioselectivity.

The stereoselectivity of aldol reactions of chiral reactants can be factorized into to three stereocontrol elements: the diastereoface selectivities of the ketone enol(ate) and aldehyde and the relative topicity of the coupling. Application of the multiplicativity rule to these elements leads to the prediction that kinetic resolution (KR) should be possible if all three stereocontrol elements are strongly biased. As a corollary, the enantioselectivity of the kinetic resolution should be switchable by a change in the sense of selectivity of any of the stereocontrol elements. This hypothesis was tested using aldehyde and ketone reactants with high diastereoface selectivities and developing reaction conditions that strongly favor either syn or anti relative topicity. The aldehyde 2 undergoes aldol reactions with near-exclusive Felkin diastereoface selectivity, and hydroxy-protected derivatives of ketone 1 (R = MOM, Et(3)Si, or Ac) undergo aldol reactions with high diastereoface selectivity to give 3,5-trans adducts. High levels of anti and syn relative topicity were obtained with dicyclohexylboron enolates and Ti(O(i)Pr)(4)Li "ate" enolates, respectively. Using these enolates, aldol reactions of (+/-)-2 with (+/-)-1 gave two of the eight possible diastereomeric adducts (3 from a diastereoselective like combination of reactant enantiomers and 4 from a diastereoselective unlike combination) predominantly (>95% of the adducts) in ratios of 0.05-20:1; boron enolates favored the like reaction (3:4, 15-20:1) and Ti "ate" enolates favored the unlike reaction (3:4, 1:10-20). Under these conditions, the ratio of like and unlike products is a measure of the mutual kinetic enantioselection (MKE) and reflects the ratio of the rate constants for the competing like and unlike reactions. For each of the four diastereomers of 1, the reactions with the highest MKEs in favor of the like (3) or unlike products (4) were repeated using highly enantioenriched ketone. These reactions occurred with the expected KR (s = 10-20) allowing selective access to enantioenriched diastereomers of 3 or 4 from (+/-)-2. These adducts are useful for polypropionate synthesis, and this design strategy for KR should be applicable to related processes.