Imidazolinium sulfonate and sulfamate zwitterions as chiral solvating agents for enantiomeric excess calculations

The synthesis of enantiopure unsymmetrical N-heterocyclic based zwitterions incorporating imidazolinium and alkylsulfonate or sulfamate groups is described. The desired compounds were prepared in good yields from 1,3-propanesultone or cyclic sulfamidates and imidazolines. The imidazolinium based zwitterions proved to be versatile chiral solvating agents for Mosher’s acid, alcohols, cyanohydrins, amino alcohols, nitro alcohols, thiols, and carboxylic acids with very high shifts in the ¹H and ¹⁹F NMR.     

Use of optically active cyclic diethyl sulfamidate 2-phosphonates as chiral synthons for the synthesis of β-substituted α-amino phosphonates

Optically active protected sulfamidate 2-phosphonates have been synthesized from either (R)- or (S)-N-benzyl-2-phosphonoserine for use as chiral synthons. These sulfamidates have been shown to undergo nucleophilic substitution with select nucleophiles, to afford following N-sulfate removal, the β-substituted α-amino-2-phosphonates. N-Sulfate removal was accomplished using boron trifluoride etherate in the presence of either n-propylthiol or N-hydroxysuccinimide allowing retention of the diethylphosphonate ester groups. Replacement of the unpleasant smelling n-propylthiol with N-hydroxysuccinimide provides higher yields of the desired products. Synthesis of β-S-substituted analogues required the use of cesium carbonate as a base. The sulfamidates described have excellent stability and have been demonstrated, using chiral HPLC, to be greater than 97% enantiomerically pure.     

Chemoselectivity Control in the Reactions of 1,2‐Cyclic Sulfamidates with Amines

Although 1,2‐cyclic sulfamidates derived from α‐methylisoserine undergo nucleophilic displacement at the quaternary center, to the best of our knowledge their behavior with amines as nucleophiles has never been explored. We have found that a broad range of amines can be used, demonstrating the scope of the reaction, and that excellent control of the chemoselectivity can be achieved. Application of this methodology for the synthesis of a chiral α,β‐diamino acid and an important piperazinone heterocycle is also presented. Additionally, we have found that DMF and DMSO behave not only as polar aprotic solvents but also as O‐nucleophilic reagents, allowing the incorporation of an oxygen atom at a quaternary center of the electrophile, with inversion of configuration.     

New routes to N-alkylated cyclic sulfamidates

BOC- and dibenzosuberyl-protected chiral and hindered cyclic sulfamidates ([1,2,3]-oxathiazolidine-2,2-dioxides) were synthesized and subsequently deprotected using trifluoroacetic acid. The resulting crystalline sulfamidates were then used in several alkylation reactions involving benzyl bromide and alcohols in a versatile route to cyclic sulfamidates with differing N-alkyl substituents.     

Reactivity of cyclic sulfamidates towards lithium acetylides: synthesis of alkynylated amines

A synthetically useful level of reactivity of cyclic sulfamidates toward acetylides is described. Ring-opening reactions of a structurally diverse set of 1,2- and 1,3-cyclic sulfamidates with a range of lithium acetylides from aliphatic, cyclic, aromatic, heteroaromatic, and functionalized alkynes proceed smoothly in a regioselective manner to give the corresponding N-sulfate intermediates. Hydrolysis of these intermediates under acidic conditions furnishes the alkynylated amines in yields ranging from 29% to 98%. The scope of the acetylenic substitution reaction with the structural variations in both the cyclic sulfamidates and alkynes is briefly examined.     

Stereo- and regio-selective one-pot synthesis of triazole-based unnatural amino acids and β-amino triazoles

Synthesis of triazole based unnatural amino acids and β-amino triazoles has been described via a stereo and regioselective one-pot multi-component reaction of sulfamidates, sodium azide, and alkynes under MW conditions. The developed method is applicable to a broad substrate scope and has significant potential for the synthesis of unnatural amino acids with a triazole side chain.     

Ring opening of cyclic sulfamidates with bromophenyl metal reagents: complementarity of sulfamidates and aziridines

Bromophenyl magnesium reagents generated via a Knochel type magnesium-halogen exchange of aryl iodides undergo regioselective ring opening of cyclic primary and secondary N-Boc sulfamidates in good to excellent yields. With secondary sulfamidates the reaction proceeds with clean inversion of the stereochemistry. This protocol complements the ring opening of aziridines with bromophenyl metal reagents and extends its scope to secondary substrates.     

Synthesis of amino thiols and isocysteines via regioselective ring opening of sulfamidates with tetrathiomolybdate

Herein we present a simple and highly efficient method for the synthesis of β and γ-amino thiols via regioselective ring opening of sulfamidates with tetrathiomolybdate 1. The generality of this methodology has been shown by synthesizing carbohydrate derived β-amino thiol. The scope and versatility of this methodology has been demonstrated by synthesizing biologically important unnatural amino acids like isocysteines in optically pure form.     

Intramolecular C-N bond formation reactions catalyzed by ruthenium porphyrins: amidation of sulfamate esters and aziridination of unsaturated sulfonamides

Ruthenium porphyrins [Ru(F(20)-TPP)(CO)] (F(20)-TPP = 5,10,15,20-tetrakis(pentafluorophenyl)porphyrinato dianion) and [Ru(Por*)(CO)] (Por = 5,10,15,20-tetrakis[(1S,4R,5R,8S)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanoanthracen-9-yl]porphyrinato dianion) catalyzed intramolecular amidation of sulfamate esters p-X-C(6)H(4)(CH(2))(2)OSO(2)NH(2) (X = Cl, Me, MeO), XC(6)H(4)(CH(2))(3)OSO(2)NH(2) (X = p-F, p-MeO, m-MeO), and Ar(CH(2))(2)OSO(2)NH(2) (Ar = naphthalen-1-yl, naphthalen-2-yl) with PhI(OAc)(2) to afford the corresponding cyclic sulfamidates in up to 89% yield with up to 100% substrate conversion; up to 88% ee was attained in the asymmetric intramolecular amidation catalyzed by [Ru(Por)(CO)]. Reaction of [Ru(F(20)-TPP)(CO)] with PhI[double bond]NSO(2)OCH(2)CCl(3) (prepared by treating the sulfamate ester Cl(3)CCH(2)OSO(2)NH(2) with PhI(OAc)(2)) afforded a bis(imido)ruthenium(VI) porphyrin, [Ru(VI)(F(20)-TPP)(NSO(2)OCH(2)CCl(3))(2)], in 60% yield. A mechanism involving reactive imido ruthenium porphyrin intermediate was proposed for the ruthenium porphyrin-catalyzed intramolecular amidation of sulfamate esters. Complex [Ru(F(20)-TPP)(CO)] is an active catalyst for intramolecular aziridination of unsaturated sulfonamides with PhI(OAc)(2), producing corresponding bicyclic aziridines in up to 87% yield with up to 100% substrate conversion and high turnover (up to 2014).     

A modular synthesis of dithiocarbamate pendant unnatural α-amino acids

Unnatural α-amino acids containing dithiocarbamate side chains were synthesized by a one-pot reaction of in situ generated dithiocarbamate anions with sulfamidates. A wide range of these anions participated in the highly regio- and stereo-selective ring opening of sulfamidates to produce the corresponding dithiocarbamate pendant α-amino acids in high yields.     

A Novel Multistep Mechanism for the Stereocontrolled Ring Opening of Hindered Sulfamidates: Mild,Green, and Efficient Reactivity with Alcohols

Cyclic hindered sulfamidates exhibited an outstanding performance in their ring‐opening reactions with alcohols and in the absence of any external activator. The mechanism of this unprecedented transformation was thoroughly studied both experimentally and theoretically. As a result, a nontrivial stepwise pathway involving solvent‐induced conversion of the sulfamidates to activated aziridinium and then to oxazolinium cations, which are finally opened at their 5‐position with inversion of configuration, is proposed. The presence of the SO₃ moiety in the sulfamidate was revealed as a “built‐in activator”. In fact, the spontaneous SO₃ cleavage takes place under the reaction conditions and avoids the subsequent step of hydrolysis after the ring opening of the sulfamidates. This is another important improvement of this methodology with respect to the standard basic conditions, allowing a greater compatibility with other functional groups. Furthermore, the carbamate group plays a key role in this mechanism. Briefly, a highly chemoselective and stereoespecific formal solvolysis of hindered sulfamidates with alcohols without further activation is described. This reaction takes place exclusively at the quaternary center with inversion of configuration, providing a new straightforward synthetic route to O‐substituted α‐methylisoserines.     

Catalytic Asymmetric Alkylation Reactions for the Construction of Protected Ethylene‐Amino and Propylene‐Amino Motifs Attached to Quaternary Stereocentres

An efficient catalytic and stereoselective method for the direct construction of protected ethylene‐amino and propylene‐amino scaffolds attached to quaternary stereocentres is reported. Preliminary investigations revealed a mild base catalysed nucleophilic ring opening of N‐sulfonyl aziridines using the commercially available phosphazene base 2‐tert‐butylimino‐2‐diethylamino‐1,3‐dimethyl‐perhydro‐1,3,2‐diazaphosphorine (BEMP) was possible and resulted in highly efficient alkylation reactions with a range of methine carbon acids. This reaction could be rendered highly asymmetric (up to 97 % ee) by employing phase‐transfer catalysis to control stereoinduction. Incorporation of alkyl substituents onto the aziridine electrophile, resulted in a highly diastereoselective (up to 30:1 d.r.) variant of this methodology. A further extension using N‐protected cyclic sulfamidates as the electrophilic component was successful with a range of pro‐nucleophiles (up to 96 % ee and 45:1 d.r.) and allowed a range of nitrogen protecting groups (carbamate, sulfonyl, phosphonyl, benzyl) to be incorporated into the alkylation adducts. Finally, the utility of the products have been demonstrated in the synthesis of useful heterocycles and compounds bearing structural components of natural products.     

Stereoselective synthesis of orthogonally protected alpha-methylnorlanthionine

[reaction: see text] As the unusual amino acid norlanthionine (nor-Lan) has previously been incorporated into cyclic peptide analogues of the ring C of lantibiotic nisin, we report here the stereoselective synthesis of the new (S,R)- and (R,R)-alpha-methylnorlanthionines (alpha-Me-nor-Lan). The orthogonally protected derivatives of these compounds have also been prepared. The key step in the synthesis of these bisamino acids was the S(N)2 opening reaction of the corresponding cyclic sulfamidates with the SH group of appropriately protected l-cysteine derivatives.     

Reactivity of cyclic sulfamidates towards sulfur-stabilised enolates. Stereocontrolled synthesis of functionalised lactams

A structurally representative series of 1,2- and 1,3-cyclic sulfamidates react with enolates derived from methyl alpha-phenylthioacetate 9b to give 5- and 6-substituted alpha-phenylthio lactams 20-24. These products provide, via the corresponding sulfoxides, an entry to alpha,beta-unsaturated lactams e.g. 12, 27, 29 and their alpha-phenylthio analogues e.g. 26 and 30. With the enantiomerically pure 1,2-cyclic sulfamidates 10, 15 and 17, these reactions all proceed with no detectable loss of stereochemical integrity.     

A unique and highly efficient method for catalytic olefin aziridination

A facile, high yielding, and stereospecific method for olefin aziridination is described. This process capitalizes on the unique reactivity of sulfamate esters in combination with 1-2 mol % Rh2(tfacam)4 and PhI(OAc)2 as the terminal oxidant to promote N-atom transfer reactions. A range of structurally and electronically disparate alkenes are found to react under conditions that employ substrate as the limiting reagent and only a slight excess of H2NSO3CH2CCl3 as the nitrogen source. The product alkoxysulfonyl aziridines are useful intermediates that react smoothly with nucleophiles to generate 1,2-amine derivatives. Following aziridine ring-opening, the N-trichloroethoxysulfonyl group can be removed under mild reductive conditions (Zn(Cu)/AcOH-MeOH) to give the corresponding 1 degrees amine. The efficient and convenient performance of this chemistry should establish it as a useful tool for synthesis.     

Chemical changes of polymeric surfaces after modification with multi-source cluster deposition

A new process for surface modification of polymers with multi-source cluster deposition apparatus has been reported in our previous work. The apparatus simultaneously supplies reactant of ammonium sulfamate and activator of energetic Ar(+) ion. In this work chemical changes are analyzed on the basis of XPS spectra and the relations of contact angle and platelet adhesion with chemical changes are discussed. Polymer film, setting on a turning holder, was irradiated by Ar(+) ions during bombardment with ammonium sulfamate clusters. The Ar(+) ion source served for activation of polymer surface and a cluster ion source supplied ammonium sulfamate molecules to react with activated surface. After thorough washing with deionized sterile water, the modified surfaces were evaluated in terms of contact angle of water, elemental composition and binding state on XPS and platelet adhesion with platelet rich plasma (PRP). The modification of polysulfone decreased the contact angle of water on surfaces from 82.6 down to 34.5 degrees. The adhesion number of platelets were decreased to one-tenth of the original surface. Ammonium, amine, sulfate and thiophene combinations were formed on the modified surfaces. The primary studies showed successful modification of polysulfone with ammonium sulfamate by assistance of Ar(+) ion irradiation. The polar groups like N-sulfate were formed on surfaces and contribute to the decrease of surface contact angle and adhesion number of platelets. Since the same process can also be applied to other polymeric materials with various substrates, combining with the features of no solvent and no topographic changes, this method might be developed in a promising way for modification of polymers.     

The sulfamate functional group as a new anchor for solid-phase organic synthesis

[reaction: see text] Sulfamate derivatives were loaded on trityl chloride resin, and two variants of cleavage were developed for this sulfamate anchor: an acid treatment to easily restore the free sulfamate and a nucleophilic treatment to generate the corresponding phenol. In addition to loading/cleavage assays and stability experiments, a model sequence of reactions was performed with the new sulfamate anchor to show its applicability in further combinatorial solid-phase synthesis of libraries of biologically relevant sulfamate derivatives.     

Water-promoted unprecedented chemoselective nucleophilic substitution reactions of 1,4-quinones with oxygen nucleophiles in aqueous micelles

Unique nucleophilic substitution and addition reactions of nitrogen and sulfur nucleophiles with 1,4-quinones in aqueous suspension with amines and thiols have recently been demonstrated by us.² However, the reactivity of oxygen nucleophiles toward nucleophilic substitution compared to nitrogen and sulfur nucleophiles ‘on water’ is not facile. An unprecedented economical, green methodology approach using ordinary laundry detergent (LD; washing powder, 0.5 mol %, reusable)/SDS as surfactant ‘in water’ for nucleophilic substitution by oxygen nucleophiles in 1,4-quinones in excellent yields has been demonstrated.     

Palladium-catalyzed carboannulation of propargylic carbonates and nucleophiles to 2-substituted indenes

A new and efficient synthesis of 2-substituted indenes has been achieved via palladium-catalyzed carboannulation of propargylic carbonates with nucleophiles in good to excellent yields. A variety of nucleophiles were tolerated in this reaction.     

Stereospecific construction of substituted piperidines. Synthesis of (-)-paroxetine and (+)-laccarin

Short and efficient enantioselective syntheses of (-)-paroxetine and (+)-laccarin are described based on the highly stereospecific cleavage of C(3)-substituted 1,3-cyclic sulfamidates.