Chiral bicyclic N,O-acetal isoserine derivatives have been synthesized by an acid-catalyzed tandem N,O-acetalization/intramolecular transcarbamoylation reaction between conveniently protected l-isoserine and 2,2,3,3-tetramethoxybutane. The delicate balance of the steric interactions between the different functional groups on each possible diastereoisomer controls their thermodynamic stability and hence the experimental product distribution. These chiral isoserine derivatives undergo diastereoselective alkylation at the α position, proceeding with either retention or inversion of the configuration depending on the relative configuration of the stereocenters. Quantum mechanical calculations revealed that a concave-face alkylation is favored due to smaller torsional and steric interactions at the bicyclic scaffold. This synthetic methodology gives access to chiral β^2,2-amino acids, attractive compounds bearing a quaternary stereocenter at the α position with applications in peptidomimetic and medicinal chemistry. Thus, enantiopure α-alkylisoserine derivatives were produced upon acidic hydrolysis of these alkylated scaffolds. In addition, α-benzylisoserine was readily transformed into a five-membered ring cyclic sulfamidate, which was ring opened regioselectively with representative nucleophiles to yield other types of enantiopure β^2,2-amino acids such as α-benzyl-α-heterofunctionalized-β-alanines and α-benzylnorlanthionine derivatives.

中文翻译：

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异丝氨酸衍生物的立体选择性烷基化和季氨基磺酸盐的亲核开环合成β2,2-氨基酸

手性双环N,O-缩醛异丝氨酸衍生物由酸催化串联N , O-缩醛化/分子内转氨甲酰化反应合成。-异丝氨酸和2,2,3,3-四甲氧基丁烷。每种可能的非对映异构体上不同官能团之间空间相互作用的微妙平衡控制了它们的热力学稳定性，从而控制了实验产物的分布。这些手性异丝氨酸衍生物在 α 位进行非对映选择性烷基化，根据立体中心的相对构型进行构型的保留或反转。量子力学计算表明，由于双环支架处较小的扭转和空间相互作用，凹面烷基化是有利的。这种合成方法可以获得手性 β ^2,2-氨基酸，在 α 位具有四元立体中心的有吸引力的化合物，可用于肽模拟物和药物化学。因此，对映体纯的 α-烷基异丝氨酸衍生物在这些烷基化支架的酸性水解中产生。此外，α-苄基异丝氨酸很容易转化为五元环环状氨基磺酸酯，其与代表性的亲核试剂进行区域选择性开环以产生其他类型的对映纯 β ^2,2 -氨基酸，例如 α-苄基-α-杂官能化-β -丙氨酸和α-苄基降羊毛硫氨酸衍生物。