Abstract
Organocatalyzed asymmetric reaction using α-isothiocyanato compounds has received much attention in the past 5 years, and significant progress has been made for three types of isothiocyanato compounds, including α-isothiocyanato amides, esters, and phosphonates. This chapter covers the recent advances of α-isothiocyanato compounds in the organocatalytic asymmetric reaction.
Keywords
- Organocatalysis
- Asymmetric synthesis
- Enantioselectivity
- α-Isothiocyanato compounds
- Cascade reaction
1. Introduction
The development of efficient approaches to construct stereochemically complex compounds by catalytic asymmetric cascade reaction has received significant attention in the past 15 years [1–3]. Isothiocyanate, a new and versatile reagent for various catalyzed asymmetric cascade reactions, was firstly prepared from thiocyanate by Hofmann in 1880 [4]. However, isothiocyanato compounds, such as 3-(2-isothiocyanatoacetyl)-oxazolidin-2-one (Figure 1,
This chapter focuses on the synthesis of stereochemically enriched compounds based on these three kinds of isothiocyanato compounds via organocatalytic asymmetric cascade reactions, including aldol/cyclization, Mannich/cyclization, Michael/cyclization, [3+2] cyclization with allenic esters, [3+2] cyclization with 2-butynedioic acid diesters, [3+2] cyclization with azodicarboxylates, as well as self-cyclization/addition with aziridines and is classified on the basis of the types of acceptors. Some common organocatalysts involved in this chapter are listed in Figure 2, including 1,2-cyclohexanediamine- and 1,2-diphenylethylenediamine-derived bifunctional catalysts
2. Cascade aldol/cyclization
In 2008, Seidel and coworkers successfully established the first cascade aldol/cyclization reaction of α-isothiocyanato imides (
Afterwards, another type of protected β-hydroxyl-α-amino acids was obtained in good results using the same strategy by Seidel and coworkers in 2010 (Scheme 2) [11]. Almost at the same time, Wang’s group also reported the organocatalytic asymmetric aldol additions of α-isothiocyanato imide (
Using the rosin-derived amine–thiourea
Shortly after this report, a similar protocol was reported by Zhao’s group in 2011 (Scheme 3) [14]. Using catalyst
Inspired by α-isothiocyanato esters or amides are efficient nucleophilic reagents to construct chiral heterocyclics [10–14], and considering the potential applications of spirocyclic oxindole skeletons which have particularly emerged as attractive synthetic targets in the field of natural products synthesis and medicinal chemistry [15–17]. 3-Isothiocyanato oxindoles (
Although isothiocyanates have previously been applied in the synthesis of cyclic aldol products [10–14], this represents the first example in the construction of spirocyclic oxindoles using 3-isothiocyanato oxindoles through direct aldol reaction. In the reaction of 3-isothiocyanato oxindoles (
Following this work, our group further disclosed a highly efficient approach for the synthesis of spiro[oxazolidine-2-thione-oxindoles] (
In 2013, our group firstly developed an asymmetric cascade aldol/cyclization reaction between α-isothiocyanato phosphonates (
Afterwards, a catalytic asymmetric 1,2-addition reaction of α-isothiocyanato phosphonates (
Recently, a novel cascade aldol/cyclization reaction of 3-isothiocyanato oxindoles with α-ketophosphonates 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). In addition, the products of this reaction can be modified to allow easy access to differently functionalized spirooxindoles.
3. Cascade Mannich/cyclization
Based on the remarkable success in the organocatalyzed asymmetric aldol reaction using α-isothiocyano imides (Scheme 2) [10], Seidel’s group reported a highly stereoselective cascade Mannich/cyclization reaction between α-isothiocyanato imides (
At the same time, a similar reaction between α-isothiocyanato imide (
In 2011, Feng’s group [24] and Wang’s group [25] independently reported highly efficient asymmetric cascade Mannich–cyclization reaction of α-isothiocyanato imides (
Feng and Wang also gave a proposed active model for the reaction in their work, respectively (Scheme 10). Feng proposed that the weakly acidic additive (
After the success in the asymmetric cascade aldol/cyclization reaction of diphenyl α-isothiocyanato phosphonate (
Organocatalytic asymmetric cascade Mannich/cyclization reaction between 3-isothiocyanato oxindoles (
Meanwhile, a similar strategy to access spirooxindole derivatives using quinine
4. Cascade Michael/cyclization
In 2011, Wang and coworkers explored the unprecedented reaction of organocatalytic asymmetric cascade Michael/cyclization reaction using α-isothiocyanato amides [28], which attribute to the stereoselectivity and reactivity of the α-isothiocyanato compounds with electron-deficient olefins is challenging. As shown in Scheme 13, rosin-derived thiourea (
Another kind of asymmetric cascade Michael/cyclization reaction between dimethylpyrazole isothiocyanato imides (
On the basis of the works from Wang’s and Barbas’ group (Scheme 13) [28, 29], organocatalytic asymmetric cascade Michael/cyclization reaction of α-isothiocyanato imides and esters (
3-Isothiocyanato oxindoles (
In 2013, an efficient asymmetric cascade Michael/cyclization reaction of 3-isothiocyanato oxindoles (
To further investigate the versatility of 3-isothiocyanato oxindoles for constructing more complex spirocyclic oxindole scaffolds, the cascade Michael/cyclization reaction of 3-isothiocyanato oxindoles (
Encouraged by our these progresses using 3-isothiocyanato oxindoles (
Recently, an organocatalytic asymmetric Michael/cyclization cascade reaction of 3-isothiocyanato oxindoles (
In 2013, catalytic asymmetric cascade Michael addition/cyclization reaction of 3-isothiocyanato oxindoles (
Having achieved remarkable success in organocatalytic asymmetric Michael/cyclization reaction with α-isothiocyanato imides and esters as versatile precursors [28, 30, 36], the asymmetric Michael/cyclization process of 3-isothiocyanato oxindoles (
In 2013, Chen and coworkers reported a formal [3+2] cycloaddition reaction between 3-isothiocyanato oxindoles (
At the same year, a similar reaction between isothiocyanato oxindoles (
Besides, β-substituted nitro olefins (
In 2014, Xie and coworkers further developed this process by employing 3-nitro-2
The development of efficient methods to construct complex molecules containing the F atoms has been attracting considerable interest due to the potential applications of this kind of compounds in biology, medicine, and agricultural chemistry as well as in materials science. Recently, Shi’s group explored a novel Cinchona alkaloid-derived multifunctional amine
In order to further expand the scope of α-isothiocyanato phosphonate in organocatalyzed asymmetric cascade reaction, the application of α-isothiocyanato phosphonate (
5. Asymmetric [3+2] cyclization of 3-isothiocyanato oxindoles with allenic esters
A novel asymmetric [3+2] cycloaddition of 3-isothiocyanato oxindoles (
6. Asymmetric [3+2] cycloaddition of 3-isothiocyanato oxindoles with 2-butynedioic acid diesters
Encouraged by the achievements in the enantioselective construction of two classes of spirooxindole derivatives (
7. Asymmetric [3+2] cyclization of 3-isothiocyanato oxindoles with azodicarboxylates
In 2013, (DHQD)2PHAL (
8. Organocatalytic asymmetric ring-opening reaction of aziridines with α-isothiocyanato imides
In 2013, Wang’s group developed a catalytic asymmetric ring-opening reaction of
In Wang’s report [45], a plausible mechanism was proposed. As shown in Scheme 21, the enolized α-isothiocyanato intermediate
9. Summary and outlook
Using α-isothiocyanato amides, esters, and phosphonates as new type of versatile reagents for the organic synthesis have been extensively studied and significant process has been made in this area over the past ten years. With these α-isothiocyanato compounds as powerful precursors, the scope of the asymmetric cascade reactions with various organocatalysts has been greatly expanded. Importantly, these developed protocols provided new access to structurally diverse and complex heterocyclic compounds which were difficult to obtain with other reactions. Despite rapid progress in organocatalytic asymmetric cascade reactions with α-isothiocyanato compounds as reagents has been made, the types of chemical reaction in this area are still limited in number. Accordingly, it might be one promising and exciting research field to develop novel asymmetric cascade reactions between the α-isothiocyanato compounds and other accepters, such as nitrosoarenes [46],
Acknowledgments
The authors wish to thank the National Natural Science Foundation of China (Nos. 21372217, 21572223 and 21572224) for the financial support.
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