Asymmetric Synthesis of Bioactive Primary Amines

描述（由申请人提供）：含有连接到立体碳的氮的手性非外消旋胺在自然界中普遍存在，并存在于许多生物活性材料中，包括药物和候选药物。相关的例子包括蛋白质和非蛋白质α-和β-氨基酸和各种生物碱。此类胺也广泛用作生物活性材料的对映选择性构建的手性结构单元。本工作的主要目的是利用对映体纯的亚磺酰亚胺[N-亚磺酰亚胺，R1 S（O）N= CR2 R3]和四种亚磺酰亚胺衍生的结构单元--β-氨基Weinreb酰胺、δ-氨基β-酮酯、3，4-二氢异喹啉和3，5-二氢-1（2 H）-异喹啉酮--对映体选择性合成生物相关的胺和生物碱。由N-亚磺酰基助剂赋予的重要优点包括（i）强大的立体定向作用;（ii）C=N键朝向亲核加成的活化;（iii）在温和条件下除去而不发生差向异构化的能力;以及（iv）通过分离非对映异构体中间体容易获得单一对映异构体。β-氨基Weinreb酰胺将用于β-氨基醛和酮的新合成，而这些醛和酮又将用于1，3-氨基醇和1，3-二胺的不对称合成，这些是重要的配体和天然产物的结构单元。多官能化哌啶和吡咯烷生物碱的对映选择性合成的新方法将利用δ-氨基β-酮酯作为结构单元。在这种情况下，新的化学将被设计用于构建反式2，6-和2，5-二取代的类似物。将侧向锂化的腈和酰胺加成到亚磺酰亚胺上，得到3，4-二氢异喹啉和3，5-二氢-1（2 H）-异喹诺酮，它们是具有通过其它方式不易获得的取代模式的结构单元。这些研究的另一个主要目的是阐明负责分子识别的因素。同时，我们将利用这种新的化学方法来简洁地合成生物相关分子或其手性非外消旋前体。靶点包括（i）密集取代的哌啶和吡咯烷生物碱，这类化合物表现出不同的生物活性;（ii）多取代脯氨酸，重要的蛋白质结构单元和修饰剂;和（iii）四氢异喹啉，有药用价值的生物碱。

DESCRIPTION (provided by applicant): Chiral nonracemic amines containing nitrogen attached to a stereogenic carbon are ubiquitous in nature and found in many biologically active materials including drugs and drug candidates. Relevant examples include proteinogenic and nonproteinogenic alpha- and beta-amino acids and diverse alkaloids. Such amines are also widely used as chiral building blocks for the enantioselective construction of bioactive materials. The principal objective of the proposed work is to employ enantiopure sulfinimines [N-sulfinyl imines, R1S(O)N=CR2R3] and four sulfinimine-derived building blocks--beta-amino Weinreb amides, delta-amino beta-ketoesters, 3,4-dihydroisoquinolines, and 3,5-dihydro-1(2H)-isoquinolones--in new methodology for the enantioselective syntheses of biologically relevant amines and alkaloids. Important advantages conferred by the N-sulfinyl auxiliary include (i) powerful stereodirecting effects; (ii) activation of the C=N bond toward nucleophilic addition; (iii) ability to be removed under mild conditions without epimerization; and (iv) ready availability of single enantiomers via separation of diastereomeric intermediates. Beta-amino Weinreb amides will be used in new syntheses of beta-amino aldehydes and ketones that in turn will be employed in the asymmetric syntheses of 1,3-amino alcohols and 1,3-diamines, important ligands and structural units of natural products. New methods for the enantioselective synthesis of polyfunctionalized piperidine and pyrrolidine alkaloids will utilize delta-amino beta-ketoesters as building blocks. In this context new chemistry will be devised for the construction of trans 2,6- and 2,5-disubstituted analogs. Addition of laterally lithiated nitriles and amides to sulfinimines provide 3,4-dihydroisoquinolines and 3,5-dihydro-1 (2H)-isoquinolones, building blocks with substitution patterns not easily accessible by other means. A further major objective in these studies is elucidation of the factors responsible for molecular recognition. Concurrently we will exploit this new chemistry in concise syntheses of biologically relevant molecules or their chiral nonracemic precursors. Targets include (i) densely substituted piperidine and pyrrolidine alkaloids, classes of compounds that exhibit diverse biological activities; (ii) polysubstituted prolines, important building blocks and modifiers of proteins; and (iii) tetrahydroisoquinolines, medicinally valuable alkaloids.