Sulfinimines Research Articles

Synthesis of Vicinal anti-Amino Alcohols from N-tert-Butanesulfinyl Aldimines and Cyclopropanols.

The stereoselective synthesis of vicinal amino alcohols derivatives from 1-substituted cyclopropanols and chiral N-tert-butanesulfinyl imines is described. Cyclopropanols are easily prepared from carboxylic esters upon reaction with ethylmagnesium bromide in the presence of titanium tetraisopropoxide and undergo carbon-carbon bond cleavage by means of diethylzinc to produce, upon base deprotonation, enolized zinc homoenolates, which react with chiral sulfinyl imines in a highly regio- and stereoselective manner.

TBADT-Mediated Photocatalytic Stereoselective Radical Alkylation of Chiral N-Sulfinyl Imines: Towards Efficient Synthesis of Diverse Chiral Amines.

Herein we describe a sustainable and efficient photocatalytic method for the stereoselective radical alkylation of chiral sulfinyl imines. By employing readily available non-prefunctionalized radical precursors and the cost-effective TBADT as a direct HAT photocatalyst, we successfully obtain diverse chiral amines with high yields and excellent diastereoselectivity under mild conditions. This method provides an efficient approach for accessing a diverse array of medicinally relevant compounds, including both natural and synthetic α-amino acids, aryl ethyl amines, and other structural motifs commonly found in approved pharmaceuticals and natural product.

A Disconnection for Rapid Access to Heterocyclic Benzylic Amines with Fully Substituted α-Carbons.

2- or 4-Pyridyl benzylic amines represent a privileged motif in drug discovery. However, the formation of heterocyclic benzylic amines with fully substituted α-carbons can require the execution of lengthy synthetic routes, which limit their application. Addition of various nucleophilic agents to Ellman's imines has been well established; however, there is no precedented literature reported for pyridyl-type nucleophiles, which are very important for medicinal chemistry. In this letter, we disclose the development of a one-step synthesis of heterocyclic benzylic amines with fully substituted α-carbons from heteroaryl halides and sulfinyl imines. Starting from 2,4-dibromopyridine, regioselective synthesis of 2- or 4-pyridyl benzylic amines could be achieved by choosing toluene or MTBE as a solvent.

Stereoselective Synthesis of Conjugated Di- and Trienamides via a Dienolate Enabled Anionic Cascade.

We report a stereoselective synthesis of conjugated di- and trienamides from the direct one pot γ-selective union of a dienolate and chiral nonconjugated and conjugated sulfinyl imines, respectively. This class of anionic cascades was uncovered as part of efforts to challenge the steric limitations of an anionic asymmetric amino-Cope rearrangement platform. Reaction scope studies have uncovered the substitution patterns essential for starting chiral tri- and Z-disubstituted conjugated and nonconjugated sulfinyl imines to be matched for the anionic cascade. Mechanistic studies indicate that, following an initial γ-dienolate Mannich attack, an intermediate 5,6-dihydropyridin-2(1H)-one is formed and then ring-opened.

Domino Reactions with Dicyanoalkenes and Fluorinated Conjugated Sulfinyl Imines. A Convenient Strategy for the Generation of Structural Diversity

AbstractDicyanoalkenes are versatile reagents in organic synthesis and they have been extensively used in a wide variety of organic transformations. However, their reactivity towards fluorinated imines remained almost unnoticed. The divergent reactivity of fluorinated conjugated sulfinyl imines with dicyanoalkenes is described herein. On the one hand, when tert‐butyl sulfinyl imines were employed, a cycloaromatization cascade process took place preferentially, rendering valuable trifluoromethyl arenes. On the other hand, the reaction with p‐tolyl sulfinyl imines mainly led to a complex tetracyclic skeleton, involving an azetidinimine rearrangement of a reaction intermediate. Finally, when 1‐indanone‐derived dicyanoalkenes were employed, the aromatization process was interrupted, rendering a new family of diene derivatives. Theoretical calculations were performed in order to shed light on the mechanistic outcome of this transformation.

Diastereoselective addition of 2-alkoxy-2-fluoroacetate to N-(tert‑butylsulfinyl)imines: Synthesis of α-alkoxy-α-fluoro-β-amino acids

A diastereoselective Mannich-type reaction of 2-alkoxy-2-fluoroacetate and N-(tert‑butylsulfinyl)imines is reported. This protocol provides a straightforward route to α-alkoxy-α-fluoro-β-amino acids in good yields and moderate to high diastereoselectivities. This approach uses readily accessible starting materials and is operationally simple. Additionally, the stereochemistry of the current reaction was different from that of the known addition of comparable nonfluorinated 2-alkoxycarboxylic esters to N-sulfinyl imines. An open transition state (rather than a closed one) is proposed to explain the stereochemical outcome.

Fluorinated Imines in Tandem and Cycloaddition Reactions.

The chemistry of fluorinated compounds has experienced extraordinary growth in recent decades due to the many and varied properties which many of the compounds that contain fluorinated groups possess. Among all of them, fluorinated chiral imines, in particular the Ellman's imines, are of great importance since they are some of the most interesting building blocks for the synthesis of a large number of enantioenriched carbocycles and heterocycles with extraordinary biological and synthetic properties. This personal account covers the most significant results obtained in our research group in the last two decades concerning asymmetric tandem reactions, paying special attention to the intramolecular aza-Michael reaction (IMAMR), diversity oriented synthesis (DOS), asymmetric tandem reactions involving a p-tolylsulfinyl group as chiral inducer and cycloaddition processes, in particular, the Pauson-Khand reaction, [2+2+2]-cycloadditions and metathesis reactions, starting mainly from enyne compounds and through the use of fluorinated chiral N-sulfinyl imines and their derivatives as starting materials.

One Step Selective Counterion Dependent Formation of Conjugated Chiral N-Sulfinylimines from Aldehydes.

We report a detailed study on the synthesis and aldehyde vinylogation applications of chiral N-sulfinyl imine phosphonate reagents. Two complementary scalable reagent routes, from trialkyl phosphites and methyl phosphonates, respectively, are presented. This reagent class enables significant streamlining in synthesis of conjugated Ellman imines from aldehydes, which can now be accomplished in a single step compared to a more classic 4-step redox-based approach. Aldehyde vinylogation optimizations have revealed significant counterion effects and unexpected competing reaction challenges that needed to be addressed to achieve high yields.

Copper-catalyzed reaction of alkyl trifluoromethyl diazoalkane for the synthesis of trifluoromethyl allenes

Generation of an unprecedented alkyl trifluoromethyl diazoalkane from sulfinyl imine via three steps has been achieved, which has been applied in a Cu-catalyzed coupling reaction with alkynes. This reaction is conducted under mild conditions and a series of variously substituted alkynes are well tolerated affording trifluoromethyl allenes in up to 91% yield, which provides an efficient way for the synthesis of trifluoromethyl allenes.

Ten-Step Total Synthesis of (-)-Andranginine.

The total synthesis of the indole alkaloid (-)-andranginine has been achieved in 10 steps. Key reactions of the synthesis include a nucleophilic addition of acetylenyl anion to chiral N-sulfinyl imine, an intramolecular N-alkylation reaction to close the C ring, and a dienyne metathesis cascade reaction to construct the DE rings. Meanwhile, 16-epi-(-)-andranginine was also obtained with the developed strategy.

Diastereoselective Hydroxylation of N-tert-Butanesulfinyl Imines with 2-(Phenylsulfonyl)-3-phenyloxaziridine (Davis Oxaziridine).

The diastereoselective α-hydroxylation of N-tert-butanesulfinyl metallodienenamine and metalloenamines with Davis oxaziridine affords α-hydroxy N-sulfinyl imines with 50-88% yield and up to 98:2 diastereomeric ratio. Dramatic changes in diastereoselectivity and stereoselectivity were observed by choice of metal bases. The mechanistic understanding for the switch in diastereoselectivity was assisted by DFT computational modeling, which suggests the facial approach is governed by aza-enolate geometry. A one-pot protocol for the asymmetric synthesis of 1,2-amino alcohols is described.

Samarium(II)‐Promoted Cyclizations of Nonactivated Indolyl Sulfinyl Imines to Polycyclic Tertiary Carbinamines

AbstractSamarium(II)‐promoted cyclizations of N‐acylated indolyl sulfinyl imines without electron‐withdrawing groups at C‐3 furnished tertiary carbinamines in good yield. Screening of the reaction conditions revealed that application of an excess of samarium diiodide in the presence of water and lithium bromide provided the cleanest reactions and the highest yields. The most striking observation during this investigation was the reductive detachment of the sulfur functional group, which most likely precedes the cyclization step. As consequence no enantioselectivity could be observed if enantiopure sulfinyl imines were employed. The mechanisms of the N−S cleavage and of the cyclization of the intermediate imines as well as the role of the additives are discussed. The presented method generates interesting polycyclic indoline derivatives; a cascade reaction involving an ethoxycarbonyl‐substituted side‐chain provided unique tetracyclic spiro‐γ‐lactams.

Simple chiral sulfinyl imine–thioether ligands for Pd-catalyzed allylic alkylation

Simple chiral sulfinyl imine–thioether ligands for Pd-catalyzed allylic alkylation

A Modular Approach to the Antifungal Sphingofungin Family: Concise Total Synthesis of Sphingofungin A and C.

Sphingofungins are fungal natural products known to inhibit the biosynthesis of sphingolipids which play pivotal roles in various cell functions. Here, we report a short and flexible synthetic approach towards the sphingofungin family. Key step of the synthesis was a decarboxylative cross‐coupling reaction of chiral sulfinyl imines with a functionalized tartaric acid derivative, which yielded the core motif of sphingofungins carrying four consecutive stereocenters and a terminal double bond. Subsequent metathesis reaction allowed for the introduction of different side chains of choice resulting in a total of eight sphingofungins, including for the first time sphingofungin C (eight steps from commercially available protected tartaric acid with an overall yield of 6 %) and sphingofungin A (ten steps). All newly synthesized derivatives were tested for their antifungal, cell‐proliferative and antiparasitic activity unraveling their structure–activity relations.

A Modular Approach to the Antifungal Sphingofungin Family: Concise Total Synthesis of Sphingofungin A and C

AbstractSphingofungins are fungal natural products known to inhibit the biosynthesis of sphingolipids which play pivotal roles in various cell functions. Here, we report a short and flexible synthetic approach towards the sphingofungin family. Key step of the synthesis was a decarboxylative cross‐coupling reaction of chiral sulfinyl imines with a functionalized tartaric acid derivative, which yielded the core motif of sphingofungins carrying four consecutive stereocenters and a terminal double bond. Subsequent metathesis reaction allowed for the introduction of different side chains of choice resulting in a total of eight sphingofungins, including for the first time sphingofungin C (eight steps from commercially available protected tartaric acid with an overall yield of 6 %) and sphingofungin A (ten steps). All newly synthesized derivatives were tested for their antifungal, cell‐proliferative and antiparasitic activity unraveling their structure–activity relations.

Two Decades of Progress in the Asymmetric Intramolecular aza-Michael Reaction.

The asymmetric intramolecular aza-Michael reaction (IMAMR) is a very convenient strategy for the generation of heterocycles bearing nitrogen-substituted stereocenters. Due to the ubiquitous presence of these skeletons in natural products, the IMAMR has found widespread applications in the total synthesis of alkaloids and biologically relevant compounds. The development of asymmetric versions of the IMAMR are quite recent, most of them reported in this century. The fundamental advances in this field involve the use of organocatalysts. Chiral imidazolidinones, diaryl prolinol derivatives, Cinchone-derived primary amines and quaternary ammonium salts, and BINOL-derived phosphoric acids account for the success of those methodologies. Moreover, the use of N-sulfinyl imines with a dual role, as nitrogen nucleophiles and as chiral auxiliaries, appeared as a versatile mode of performing the asymmetric IMAMR.

Diastereoselective Synthesis of Morpholine Derivatives from Grignard Reagents and N-Sulfinyl Imines

AbstractThe stereoselective synthesis of substituted morpholine derivatives has been achieved through a two-step process involving diastereoselective addition of a Grignard reagent to a sulfinyl imine, followed by cyclization.

Photoredox-Catalyzed Radical Addition to Glyoxylate-Derived N-Sulfinyl Imines

Key words photoredox catalysis - sulfinyl imines - carboxylic acids - sulfinyl amino acids

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles.

The synthesis of nitrogen-containing heterocycles, including natural alkaloids and other compounds presenting different types of biological activities have proved to be successful employing chiral sulfinyl imines derived from tert-butanesulfinamide. These imines are versatile chiral auxiliaries and have been extensively used as eletrophiles in a wide range of reactions. The electron-withdrawing sulfinyl group facilitates the nucleophilic addition of organometallic compounds to the iminic carbon with high diastereoisomeric excess and the free amines obtained after an easy removal of the tert-butanesulfinyl group can be transformed into enantioenriched nitrogen-containing heterocycles. The goal of this review is to the highlight enantioselective syntheses of heterocycles involving the use of chiral N-tert-butanesulfinyl imines as reaction intermediates, including the synthesis of several natural products. The synthesis of nitrogen-containing heterocycles in which the nitrogen atom is not provided by the chiral imine will not be considered in this review. The sections are organized according to the size of the heterocycles. The present work will comprehensively cover the most pertinent contributions to this research area from 2012 to 2020. We regret in advance that some contributions are excluded in order to maintain a concise format.

Diastereoselectivity of the Addition of Propargylic Magnesium Reagents to Fluorinated Aromatic Sulfinyl Imines.

The addition of propargylmagnesium bromide to fluorinated aromatic sulfinyl imines gave homopropargyl amines with total regio- and diastereoselection. Complete reversal of diastereoselectivity can be achieved in some cases using coordinating (THF) or noncoordinating (DCM) solvents. Substituted propargylic magnesium reagents have been also tested toward fluorinated aryl sulfinyl imines affording chiral homoallenyl amines with good yields and selectivity control. DFT calculations helped to rationalize the origin of the experimental regio- and diastereoselectivities observed in each case.