Catalytic Aldol–Cyclization Cascade of 3-Isothiocyanato Oxindoles with α-Ketophosphonates for the Enantioselective Synthesis of β-Amino-α-hydroxyphosphonates

Abstract

A cascade aldol-cyclization reaction between 3-isothiocyanato oxindoles and α-ketophosphonates has been developed for the synthesis of β-amino-α-hydroxyphosphonate derivatives. Catalyzed by a quinine-based tertiary amino-thiourea derivative, this reaction delivers 2-thioxooxazolidinyl phosphonates based on a spirooxindole scaffold bearing two contiguous quaternary stereogenic centers in high yields with excellent diastereo- (up to >20:1 dr) and enantioselectivities (up to >99:1 er).

Recent Advances in the Construction of Phosphorus‐Substituted Heterocycles, 2009–2019

“…Currently, the catalytic asymmetric phospha‐Michael, phospha‐Mannich [80.81,89,90,92] and phospha‐aldol reactions have demonstrated broad applications in the construction of enantioenriched phosphorus‐substituted heterocycles featuring a phosphorus‐containing stereocenter . Some reactions involving heterocycle ring formation based on phosphorus compounds bearing C( sp 3 )−P and C( sp 2 )−P bonds have also been employed to synthesize optically active carbon‐centered and phosphorus‐centered phosphorus‐substituted heterocycles. Identifying effective chiral catalysts and highly efficient catalytic asymmetric systems for the development of asymmetric synthesis of such compounds will no doubt become the future state of the art in this field.…”

“…In 2015, Mukherjee and co‐workers established a cascade aldol/cyclization reaction of 3‐isothiocyanto oxindoles 484 and α‐ketophosphonates 485 , which allowed the efficient construction of β‐amino‐α‐hydroxyphosphonate derivatives 486 that feature both a phosphonyl group and an oxindole framework . Bifunctional quinine‐thiourea 255 catalyzed this reaction well to afford spirooxindoles 486 bearing two contiguous quaternary stereogenic centers in high yields, with up to >20:1 dr and >98% ee values (Scheme ).…”

Organocatalyzed Asymmetric Reaction Using α-Isothiocyanato Compounds

“…Recently, a novel cascade aldol/cyclization reaction of 3-isothiocyanato oxindoles with αketophosphonates was disclosed by Mukherjee's group (Scheme 8) [21]. This protocol provides an alternative approach to the β-amino-α-hydroxyphosphonate derivatives which contains a spirooxindole scaffold bearing two contiguous quaternary stereogenic centers in high yields with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to >99:1 er).…”

“…3-Isothiocyanato oxindoles (2) are important reagents for the stereoselective construction of structurally diverse spirocyclic oxindoles via cascade aldol/cyclization process [7,18,21,31] and Mannich/cyclization process [26,27,31]. It is worthy to note that organocatalytic asymmetric cascade Michael/cyclization reactions using 3-isothiocyanato oxindoles as donors to construct densely functionalized spirooxindoles derivatives rapidly appeared during the past four years.…”

Recent Advances in 3-Isothiocyanato Oxindoles Engaged Asymmetric Cascade Reactions

“…3-异硫氰酸酯氧化吲哚能与简单的酮及靛红 [12] 反 应, 此外也可以和酮的衍生物作用. 2015 年, Mukherjee 小组 [13] 成功实现了奎宁衍生的三级胺硫脲催化剂 11 促 进的 3-异硫氰酸酯氧化吲哚 1 与 α-酮膦酸酯 10 的串联 Aldol/Cyclization 反应, 高立体选择性地合成了含有两 (1) Nutlin [17] , 一种基于咪唑骨架的可 以有效抑制 p53/E3 泛素连接酶 Mdm2 之间相互作用的 拮抗剂; (2) MI-219 [18] , 基于吡咯啉螺环氧化吲哚的 p53/ Mdm2 抑制剂. 鉴于此, 该方法将为药物化学领域中设 计和合成新的潜在抗肿瘤试剂提供一条非常重要的途 径 .…”