69726-27-8

Upstream product

• 15934-34-6 (+)-(S)-Phenyl-N-methylbenzolsulfonimidat 
• 917-54-4 methyllithium 
• 131865-69-5 (+)-(S)-S-(1-cyclopen-1-ylmethyl)-N-methyl-S-phenylsulfoximine 
• 78-84-2 isobutyraldehyde 
• 96-09-3 styrene oxide 
• 1333171-83-7 C₁₅H₂₁NO₃S 
• 1333171-87-1 C₁₆H₂₃NO₃S 
• 1333171-89-3 C₁₈H₂₇NO₃S 
• 1333171-91-7 C₂₁H₂₅NO₄S 
• 1333171-92-8 C₂₀H₂₃NO₃S 
• 1333171-93-9 C₁₈H₂₅NO₃S 
• 122-60-1 Phenyl glycidyl ether 
• 873-55-2 sodium benzenesulfonate 
• 74-89-5 methylamine 

Downstream Products

• 618-41-7 Benzenesulfinic acid 
• 74-89-5 methylamine 
• 83706-27-8 N-methyl-S-phenylsulfonimidoyl fluoride 
• 15934-34-6 (+)-(S)-Phenyl-N-methylbenzolsulfonimidat 
• 17247-02-8 N,N'-Dimethylbenzolsulfonimidamid 
• 15934-21-1 N-methyl-S-phenylsulfonimidoyl chloride 

Relevant academic research and scientific papers

A study of the reactivity of S(VI)-F containing warheads with nucleophilic amino-acid side chains under physiological conditions

Sulfonyl fluorides (SFs) have recently emerged as a promising warhead for the targeted covalent modification of proteins. Despite numerous examples of the successful deployment of SFs as covalent probe compounds, a detailed exploration of the factors influencing the stability and reactivity of SFs has not yet appeared. In this work we present an extensive study on the influence of steric and electronic factors on the reactivity and stability of the SF and related SVI-F groups. While SFs react rapidly with N-acetylcysteine, the resulting adducts were found to be unstable, rendering SFs inappropriate for the durable covalent inhibition of cysteine residues. In contrast, SFs afforded stable adducts with both N-acetyltyrosine and N-acetyllysine; furthermore, we show that the reactivity of arylsulfonyl fluorides towards these nucleophilic amino acids can be predictably modulated by adjusting the electronic properties of the warhead. These trends were largely conserved when the covalent reaction occurred within a protein binding pocket. We have also obtained a crystal structure depicting covalent modification of the catalytic lysine of a tyrosine kinase (FGFR1) by the ATP analog 5′-O-3-((fluorosulfonyl)benzoyl)adenosine (m-FSBA). Highly reactive warheads were demonstrated to be unstable with respect to hydrolysis in buffered aqueous solutions, indicating that warhead reactivity must be carefully tuned to provide optimal rates of protein modification. Our results demonstrate that the reactivity of SFs complements that of more commonly studied acrylamides, and we hope that this work spurs the rational design of novel SF-containing covalent probe compounds and inhibitors, particularly in cases where a suitably positioned cysteine residue is not present.

Asymmetric synthesis of densely functionalized medium-ring carbocycles and lactones through modular assembly and ring-closing metathesis of sulfoximine-substituted trienes and dienynes

An asymmetric synthesis of densely functionalized 7-11-membered carbocycles and 9-11-membered lactones has been developed. Its key steps are a modular assembly of sulfoximine-substituted C- and O-tethered trienes and C-tethered dienynes and their Ru-catal

Consecutive reactions with sulfoximines: Straightforward synthesis of substituted 5,5-spiroketals

An efficient synthesis of 5,5-spiroketals (i.e., 1,6-dioxa-spiro[4.4]nonane derivatives) is described from 2-(sulfonimidoyl-methylene)tetrahydrofurans involving a consecutive epoxide opening/oxa-Michael spiroketalization sequence. This methodology was applied to the very direct synthesis of chalcogran, a beetle pheromone. Georg Thieme Verlag Stuttgart ? New York.

Hydrolysis rates of alkyl and aryl sulfinamides: evidence of general acid catalysis

Sulfinamides are important in enantioselective synthesis, as rare post-translational modifications of proteins and as isosteres of the amide bond. Little is known about the rates of hydrolysis for aliphatic sulfinamides or the mechanism of hydrolysis. In this Letter, we show that sulfinamides hydrolyse by predominantly a non-specific acid/base catalysis with phosphate buffer but by varying the buffer concentration, it was possible to determine the hydrolysis rates of a range of sulfinamides with water through non-linear least squares regression.

Asymmetric synthesis of protected β-substituted and β,β-disubstituted β-amino acids bearing branched hydroxyalkyl side chains and of protected 1,3-amino alcohols with three contiguous stereogenic centers from allylic sulfoximines and aldehydes

We describe a new method for the asymmetric synthesis, from allylic sulfoximines and aldehydes, of N,O-protected, cyclic and acyclic, β-substituted and β,β-disubstituted δ-hydroxy-β-amino acids and of N,O-protected 1,3-amino alcohols, both possessing three contiguous stereogenic centers. Treatment of enantiomerically pure, acyclic allylic sulfoximines with aldehydes after successive lithiation and titanation afforded sulfonimidoyl-substituted homoallylic alcohols with high regio- and diastereoselectivities. Diastereomerically pure, cyclic, sulfonimidoyl-substituted homoallylic alcohols were synthesized in a similar manner from the corresponding enantiomerically pure, cyclic allylic sulfoximines and isobutyraldehyde. A highly diastereoselective amination of the sulfonimidoyl-substituted homoallylic alcohols with the generation of secondary and tertiary C atoms and formation of the sulfonimidoyl-substituted, protected 1,3-amino alcohols (oxazinones) was achieved by the carbamate method, through cyclization of the corresponding carbamates after their lithiation with nBuLi. The sulfonimidoyl-substituted, monocyclic and bicyclic oxazinones were converted into protected, acyclic and cyclic, β-substituted and β,β-disubstituted β-amino acids and protected 1,3-amino alcohols by two different routes: the carbanion route and the substitution route. The carbanion route involves: (1) a double lithiation of the protected β-amino sulfoximines, (2) treatment of the dilithiated sulfoximines with electrophiles, and (3) reductive removal of the sulfonimidoyl group. By the carbanion route, double lithiation of the sulfonimidoyl-substituted oxazinones with nBuLi gave the corresponding dilithium salts, which reacted readily with a number of electrophiles to give the corresponding α-substituted sulfoximines in good yields. Reduction of the sulfoximines with Raney nickel afforded the corresponding protected monocyclic and bicyclic 1,3-amino alcohols and the protected acyclic and cyclic β-amino acids in good yields. The substitution route involves: (1) a facile substitution of the sulfonimidoyl group by a Cl atom, and (2) a substitution of the Cl atom of the protected β-amino chlorides by a cyano group. Treatment of the sulfoximines with ClCO2Me readily afforded the corresponding β-amino chlorides in good yields, and so treatment of alkyl sulfoximines with chloroformates seems to be a general method for the replacement of an N-methylsulfonimidoyl group by a Cl atom. Introduction of a cyano group was achieved through treatment of chlorides with NaCN, which gave the corresponding β-amino nitriles in good yields. Finally, hydrolysis of the nitriles afforded the protected acyclic and cyclic, β-substituted and β,β-disubstituted β-amino acids. Treatment of the protected β-amino sulfoximines with ClCO2Me gave - besides the corresponding chlorides - methyl (S)-N-phenyl-sulfinylcarbamate with ≥ 99% ee in good yield. Treatment of the sulfinamide with MeMgCl afforded (S)-methyl phenyl sulfoxide with 97% ee, and this could be converted with complete retention of configuration into (S)-N,S-dimethyl-S-phenylsulfoximine, the starting material for the synthesis of the allylic sulfoximines used in this work. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Asymmetric synthesis of fused bicyclic α-amino acids having a hexahydro-cyclopenta[c]pyridine skeleton via intramolecular Pauson-Khand reaction of 1-sulfonimidoyl-substituted 5-azaoct-1-en-7-ynes

An asymmetric synthesis of fused bicyclic amino acids having a hexahydro-cyclopenta[c]pyridine skeleton and carrying besides an enone structural element a substituent at the β-position is described. The key steps of the synthesis are a highly selective al

Preparation, properties, and chemical reactivity of α-nitrosulfoximines, chiral analogues of α-nitrosulfones

Racemic N-methyl-S-(nitromethyl)-S-phenylsulfoximine (2) was prepared in 87% yield via alkaline nitration of N,S-dimethyl-S-phenylsulfoximine. Optically active N-methyl-S-(nitromethyl)-S-phenylsulfoximine (both enantiomers) was prepared in similar fashion. Reaction of racemic 2 with p-chlorophenyl isocyanate and a catalytic quantity of triethylamine in the presence of furan afforded dihydrofuroisoxazole 5, the product of nitrile oxide cycloaddition, in 42% yield (65:35 diastereomer ratio). Reaction of the dihydrofuroisoxazole 5 with phenyllithium and methyllithium afforded replacement of the sulfoximine group by phenyl and methyl, respectively. Reaction of racemic 2 with aromatic isocyanates and potassium carbonate afforded C-acylation products in 70-78% yield which existed as the ylide tautomers 9a,b. Methylation of racemic 2 afforded the C-alkylate N-methyl-S-(1-nitroethyl)-S-phenylsulfoximine (13), existing as the neutral tautomer.

Asymmetric synthesis of isocarbacyclin based on the olefination-isomerization-coupling process with chiral sulfoximines

An asymmetric synthesis of isocarbacyclin (2) was achieved from ketone 7 by the olefination-isomerization-coupling process with chiral sulfoximines. The vinylic sulfoximine 6 (≥98% de) was prepared from ketone 7 and lithiosulfoximine 8 by an asymmetric olefination via an addition-elimination process. Model experiments, aiming at a rationalization of the asymmetric induction in the elimination of β-hydroxysulfoximines, with ketone 12 and lithiosulfoximine ent-8 revealed formation of the silyl ether 15 as an intermediate which eliminated LiOSiMe3 upon reaction with nBuLi under formation of (S,Z)-alkene 17 (≥98% de). Reaction of the C,O-dilithiosulfoximine 19 with CISiMe3 led to elimination of LiOSiMe3 and also gave 17 (≥98% de). Methylation of 19, however, furnished the corresponding α-methyl-substituted β-hydroxysulfoximines, 20 and 21, in a ratio of 75:25. Isomerization of sulfoximine 6 gave the allylic sulfoximine 5 (96% de) whose absolute configuration was determined by X-ray structure analysis. Cross-coupling reaction of 5 with cuprate 23 delivered with high regioselectivity alkene 25. A similar reaction of 5 with the organocopper reagent 26, which was prepared from (benzyloxy)methylmagnesium chloride, in the presence of BF3 · OEt2 and halide afforded alkene 27. Ketone 28 is a potential starting material for the asymmetric synthesis of 3-oxaisocarbacyclin. Besides alkenes 25 and 27 sulfinamide 24 (97% ee), whose conversion to 8 has been already described, was isolated in 90% yield. The key step in the sequence leading to the construction of the ω-side chain was the deprotonation of ketone 4b with a complex of lithium (R.R)-bis(α-phenylethyl)amide and lithium chloride, 29 - LiCl, which gave enolate 3. The use of ent-29 - LiCl in the deprotonation of 4b afforded the isomeric enolate 30. Enolates 3 and 30 were trapped as the silyl ethers 31 (90% ie) and 32 (92% ie), respectively. The aldol reaction of 3 with (E)-octenal proceeded highly selective in regard to C-12 but unselective in regard to C-13 and gave aldols 34 (42%) and epi-34 (36%). It was at the stage of the aldol reaction of 3 where the unwanted diastereomers 35 and epi-35, stemming from 30, could be separated. Reduction of ketones 34 and epi-34 afforded diols 36 (≥98% de) and 37 (93% de), respectively. The Pd-catalyzed rearrangement of the allylic diacetates 39 and 41 was highly stereoselective (≥98% de) but incomplete and led to formation of mixtures of 40 and 39 as well as of 42 and 41 in ratios of 84:16 and 86:14, respectively. A two-step oxidation of alcohol 43, contaminated by 5% of the isomeric alcohol stemming from acetate 39, via aldehyde 44 gave after purification by crystallization isocarbacyclin (2) in 38% yield. Diol 45, having the undesired (15R) configuration, was selectively oxidized with dichlorodicyanobenzoquinone to enone 46 (81%).

Experimental and Computational Evidence for the Formation of Iminopersulfinic Acids

An experimental and computational study of the reactions of singlet oxygen with N-substituted sulfenamides is reported. Intermediates capable of epoxidizing norbornene were observed during the photooxidations of three sulfenamides. These results are used to argue for formation of iminopersulfinic acids. The structural integrity of two iminopersulfinic acids was supported by their successful location at the MP2/6-31G* level of theory. Furthermore, the inability to locate computationally significant persulfinimide precursors suggests that the iminopersulfinic acids form by enelike reactions involving near-simultaneous addition of singlet oxygen to sulfur and hydrogen abstraction.

Palladium-catalyzed rearrangement of allylic sulfoximines: Application to the asymmetric synthesis of chiral allylic amines

The palladium(0)-catalyzed reactions of the primary and secondary allylic sulfoximines 7, 9, 11, 13, 15, 17, and 19 gives allylic sulfinamides without 1,3-allylic rearrangement. These compounds were not isolated but were converted to their corresponding N-tosyl allylic amines, primary and secondary 8, 10, 12, 14, 16, 18, and 20, respectively. In the case of the optically active secondary allylic sulfoximines 17 and 19, chiral N-tosyl allylic secondary amines were formed in high enantiomeric purities.