Asymmetric Synthesis of Bioactive Primary Amines

描述（由申请人提供）：手性非外消旋胺含有附着在立体碳上的氮，在自然界中无处不在，存在于许多生物活性材料中，包括药物和候选药物。相关的例子包括产生蛋白质和非产生蛋白质的α和β氨基酸以及各种生物碱。这类胺也被广泛用作生物活性材料对映选择性构建的手性构建块。提出的工作的主要目的是采用对映纯亚亚胺[N-亚胺基亚胺，R1S(O)N=CR2R3]和四种亚亚胺衍生的构建块-氨基Weinreb酰胺，三角氨基β -酮酯，3,4-二氢异喹啉和3,5-二氢-1(2H)-异喹诺酮-在新的方法中对映选择性合成生物相关胺和生物碱。n -亚砜基助剂的重要优点包括：(1)强大的立体定向效应；（ii） C=N键向亲核加成的活化；（iii）在温和条件下不进行外聚化的能力；（iv）通过分离非对映体中间体获得单对映体。-氨基Weinreb酰胺将用于合成新的-氨基醛和酮，而这些醛和酮又将用于不对称合成1,3-氨基醇和1,3-二胺，这些是天然产物的重要配体和结构单元。对映选择性合成多功能化哌啶和吡咯烷生物碱的新方法将利用-氨基-酮酯作为构建块。在这种情况下，新的化学将被设计用于构建反式2,6-和2,5-二取代类似物。将横向锂化的腈和酰胺添加到亚亚胺中，可以得到3,4-二氢异喹啉和3,5-二氢-1 (2H)-异喹诺酮，这是具有替代模式的构建单元，不易通过其他方法获得。这些研究的另一个主要目标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简明合成生物相关分子或其手性非外消旋前体。目标包括(i)密集取代的哌啶和吡咯烷类生物碱，这类化合物具有多种生物活性；（ii）多取代脯氨酸，蛋白质的重要组成部分和修饰剂；（三）四氢异喹啉类，具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.