Asymmetric Synthesis of Bioactive Primary Amines

描述(申请人提供)：手性非外消旋胺，含有连接在立体碳上的氮，在自然界中普遍存在，并在许多生物活性物质中发现，包括药物和候选药物。相关的例子包括蛋白质来源的和非蛋白质来源的α-和β-氨基酸以及各种生物碱。这类胺还被广泛用作手性构建块，用于生物活性材料的对映选择性构建。这项拟议工作的主要目标是将对映体亚胺[N-亚磺酰亚胺，R1S(O)N=CR2R3]和四个亚磺亚胺衍生的构筑块--β-氨基Weinreb酰胺、β-氨基-β-酮酸酯、3，4-二氢异喹啉和3，5-二氢-1(2H)-异喹诺酮--用于生物相关胺和生物碱的对映选择性合成的新方法。N-亚磺基助剂的重要优点包括(I)强大的立体定向效应；(Ii)C=N键向亲核加成反应的激活；(Iii)能够在温和的条件下消除而不发生异构化；以及(Iv)通过分离非对映异构体中间体而容易获得单一对映体。β-氨基Weinreb酰胺将用于β-氨基醛和酮的新合成，进而用于天然产物的重要配体和结构单元1，3-氨基醇和1，3-二胺的不对称合成。多官能团化的哌啶和吡咯烷生物碱的对映选择性合成的新方法将利用β-氨基-β-酮酯作为构筑基块。在此背景下，将为构建反式2，6-和2，5-二取代类似物设计新的化学。将侧向锂化腈和酰胺加到亚磺胺中，得到3，4-二氢异喹啉和3，5-二氢-1(2H)-异喹诺酮，它们的取代模式不容易通过其他方法获得。这些研究的另一个主要目标是阐明影响分子识别的因素。同时，我们将在生物相关分子或它们的手性非外消旋前体的简明合成中开发这一新的化学。目标包括(I)密集取代的哌啶和吡咯烷生物碱，这是一类显示出不同生物活性的化合物；(Ii)多取代脯氨酸，重要的蛋白质构建块和修饰剂；以及(Iii)四氢异喹啉，医学上有价值的生物碱。

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.