Stereoselective addition of alpha-sulfinyl carbanions to N-p-tolylsulfinylketimines: synthesis of optically pure 1,2,2'-trialkyl-2-aminoethanols

The reactions of lithium carbanions derived from both enantiomers of methyl (1) and ethyl p-tolyl sulfoxide (2) with (S)-N-arylsulfinylketimines 3 and 4 took place in a highly stereoselective manner and good isolated yields. The configuration of the carbon bonded to nitrogen relies exclusively on the N-sulfinylimine configuration. When ethyl p-tolyl sulfoxide (2) is use as nucleophile, two chiral centers are created simultaneously, where the configuration of the carbon bonded to the sulfur is mainly controlled by 2. The asymmetric induction increases with the temperature, being total at room temperature in the case of the matched pair of reactants. A non-oxidative Pummerer reaction on the obtained aminosulfoxides allows a straightforward synthesis of optically pure 1,2-ethanolamines with one or two chiral centers, including amino alcohols with a bulky quaternary carbon bonded to the amine group.     

Highly stereoselective benzylation of N-sulfinylketimines

The benzylation of N-sulfinyl ketimines with 2-(p-tolylsulfinyl)ethylbenzene and LDA afford t-alkylamines in good yields. The configuration at each one of the new chiral centers simultaneously created in this reaction is controlled by the configuration of the sulfinyl groups at the nucleophile and electrophile, respectively. Thus, the reactions of the (S)-sulfoxide 6 with the N-(S)-sulfinylketimines 3 only yield the anti diastereoisomers 18, whereas the syn diastereoisomers 19 are exclusively formed in reactions of (S)-6 with N-(R)-sulfinylketimines 3. After a two-step desulfinylation process ((i) TFA, (ii) Ra-Ni), this reaction provides a procedure for synthesizing any epimer of alpha,alpha-dibranched beta-alkylarylamines in optically pure form by choosing the configuration of the starting materials. A similar behavior is observed for carbanions derived from the O-protected 2-(p-tolylsulfinyl) benzyl alcohol 7 thus allowing the synthesis of the optically pure anti- and syn-1,2-amino alcohols containing a chiral quaternary carbon adjacent to the nitrogen.     

Evidence for a nonradical pathway in the photoracemization of aryl sulfoxides

Photolysis of (R(S),S(C))-1-deuterio-2,2-dimethylpropyl p-tolyl sulfoxide provides mainly (S(S),S(C))-1-deuterio-2,2-dimethylpropyl p-tolyl sulfoxide at low conversion, though the other two stereoisomers are formed to smaller extents. Thus, the predominant process leading to sulfur inversion yields only sulfur inversion, without inversion of the adjacent CHD stereogenic center. This is taken as evidence for a mechanism for photochemical epimerization of sulfoxides that does not involve homolytic alpha-cleavage chemistry.     

Adventures in sulfur-nitrogen chemistry

This account reviews our efforts over the past 37 years to understand the chemistry of a select group of sulfur-nitrogen compounds including sulfinimines (N-sulfinyl imines) and N-sulfonyloxaziridines. Our early exploration of the thermal properties of sulfenamides, a class of sulfur-nitrogen compounds about which little was known, resulted in a new procedure, the silver-assisted method, for the construction of sulfenimines (N-sulfenyl imines). Selective oxidations of these compounds resulted in the production of N-sulfinyl imines (sulfinimines) and N-sulfonyloxaziridines. N-Sulfonyloxaziridines turned out to be a new class of aprotic neutral oxidizing reagents. Enantiomerically pure examples afford high ee values in the oxidation of enolates to alpha-hydroxy carbonyl compounds and in the oxidation of sulfides and selenides to sulfoxides and selenoxides. Additions of organometallic reagents to enantiomerically pure sulfinimines provide the best and most versatile method for the asymmetric construction of the carbon-nitrogen stereocenters found in many biologically active compounds. Sulfinimine-derived chiral building blocks provide efficient access to many classes of nitrogen heterocycles including aziridines, 2H-azirines, pyrrolidines, and piperidines.     

Development of new synthetic methods with aryl 1-chlorovinyl sulfoxides

Aryl 1-chlorovinyl sulfoxides were easily synthesized from ketones and aldehydes with aryl chloromethyl sulfoxide in three-steps with high overall yields. Low-temperature treatment of the aryl 1-chlorovinyl sulfoxides with alkyllithium or a Grignard reagent gave alkylidene carbenoids via a sulfoxide-metal exchange reaction. From the alkylidene carbenoids, acetylenic compounds, tetra-substituted olefins, and allenes were synthesized. Enolization of alpha-chloro alpha-sulfinyl ketones, which were synthesized from methyl esters and chloromethyl phenyl sulfoxide, is another method for the generation of aryl 1-chloroalkyl sulfoxides. Treatment of 1-chlorovinyl phenyl sulfoxides so generated with t-BuLi followed by some nucleophiles having an acidic hydrogen gave one-carbon elongated carboxylic acids and their derivatives. Conjugate addition of some carbanions with 1-chlorovinyl p-tolyl sulfoxides was found to have taken place. For example, reaction of 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium gave high yields of cyclic enaminonitriles. Acidic treatment of the enaminonitriles afforded good yields of 4,4-disubstituted 2-cyclopentenones. By using unsymmetrical ketones and optically pure chloromethyl p-tolyl sulfoxide, this procedure suggests a good method for an asymmetric synthesis of optically pure 4,4-disubstituted 2-cyclopentenones. This method achieved an asymmetric total synthesis of (+)-alpha-cuparenone starting from methyl 4-methylphenyl ketone and (R)-(-)-chloromethyl p-tolyl sulfoxide. A novel synthesis of 2,4,4-trisubstituted 2-cyclopentenones is also successful using cyanomethyllithium and its homologues. Conjugate addition of the lithium enolate of tert-butyl acetate and its homologues gave high yields of the adduct, 3,3-disubstituted esters. Synthesis of various kinds of carboxylic acids and their derivatives and lactones was realized from the adducts.     

General route to racemic and enantiomeric carbo- and heterocyclic vinyl sulfoxides via tandem Michael addition/Horner olefination of alpha-phosphorylvinyl sulfoxides

A new one-pot synthesis of heterocyclic and carbocyclic vinyl sulfoxides has been developed which involves reaction of alpha-phosphorylvinyl sulfoxides with carbonyl compounds bearing oxygen, nitrogen, and carbon nucleophilic centers. Use of optically active alpha-phosphorylvinyl p-tolyl sulfoxides in this tandem Michael addition/Horner olefination reaction leads to the corresponding optically active cyclic sulfoxides. In this way, a variety of optically active chromene, pyrrolizine, chinoline, and cyclopentene sulfoxides have been efficiently prepared.     

One-electron versus two-electron mechanisms in the oxidative addition reactions of chloroalkanes to amido-bridged rhodium complexes

The compound syn-[{Rh(mu-NH{p-tolyl})(CNtBu)(2)}(2)] (1) oxidatively adds C--Cl bonds of alkyl chlorides (RCl) and dichloromethane to each metal centre to give the cationic complexes syn-[{Rh(mu-NH{p-tolyl})(eta(1)-R)(CNtBu)(2)}(2)(mu-Cl)]Cl and anti-[{Rh(mu-NH{p-tolyl})Cl(CNtBu)(2)}(2)(mu-CH(2))]. Reaction of 1 with the chiral alkyl chloride (-)-(S)-ClCH(Me)CO(2)Me (R*Cl) gave [{Rh(mu-NH{p-tolyl})(eta(1)-R*)(CNtBu)(2)}(2)(mu-Cl)]Cl ([3]Cl) as an equimolecular mixture of the meso form (R,S)-[3]Cl-C(s) and one enantiomer of the chiral form [3]Cl-C(2). This reaction, which takes place in two steps, was modeled step-by-step by reacting the mixed-ligand complex syn-[(cod)Rh(mu-NH{p-tolyl})(2)Rh(CNtBu)(2)] (4) with R*Cl, as a replica of the first step, to give [(cod)Rh(mu-NH{p-tolyl})(2)RhCl(eta(1)-R*)(CNtBu)(2)] (5) with racemization of the chiral carbon. Further treatment of 5 with CNtBu to give the intermediate [(CNtBu)(2)Rh(mu-NH{p-tolyl})(2)RhCl(eta(1)-R*)(CNtBu)(2)], followed by reaction with R*Cl reproduced the regioselectivity of the second step to give (R,S)-[3]Cl-C(s) and [3]Cl-C(2) in a 1:1 molar ratio. Support for an S(N)2 type of reaction with inversion of the configuration in the second step was obtained from a similar sequence of reactions of 4 with ClCH(2)CO(2)Me first, then with CNtBu, and finally with R*Cl to give [(CNtBu)(2)(eta(1)-CH(2)R)Rh(mu-NH{p-tolyl})(2)(mu-Cl)Rh(eta(1)-R*)(CNtBu)(2)]Cl (R = CO(2)Me, [7]Cl) as a single enantiomer with the R configuration at the chiral carbon. The reactions of 1 with (+)-(S)-XCH(2)CH(CH(3))CH(2)CH(3) (X = Br, I) gave the related complexes [{Rh(mu-NH{p-tolyl})(eta(1)-CH(2)CH(CH(3))CH(2)CH(3))(CNtBu)(2)}(2)(mu-X)]X, probably by following an S(N)2 profile in both steps.     

Asymmetric synthesis of alpha-amino 1,3-dithioketals from sulfinimines (N-sulfinyl imines). Synthesis of (2S,3R)-(-)-3-hydroxy-3-methylproline

[reaction: see text] N-Sulfinyl alpha-amino 1,3-dithioketals are prepared in high de and good yield by treating sulfinimines with lithio-1,3-dithianes. Selective removal of the N-sulfinyl or the thioketal groups affords stable alpha-amino 1,3-dithioketals and N-sulfinyl alpha-amino ketones, respectively. This new sulfinimine-derived chiral building block is employed in the asymmetric synthesis of polyoxypeptin amino acid (2S,3R)-(-)-3-hydroxy-3-methylproline.     

Asymmetric synthesis of aziridine 2-phosphonates from enantiopure sulfinimines (N-sulfinyl imines). Synthesis of alpha-amino phosphonates

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure sulfinimines, has been developed for the asymmetric synthesis of aziridine 2-phosphonates. Best results involve cyclization of the syn and anti diastereomerically pure alpha-chloro-beta-amino phosphonates to cis- and trans-N-sulfinyl aziridine 2-phosphonates, respectively, with n-BuLi. A transition-state hypothesis is proposed wherein the chloromethylphosphonate anion adds to the C-N bond on the side that is opposite the bulky p-tolyl sulfinyl group. The N-sulfinyl group is easily removed by treatment with MeMgBr or TFA/MeOH, which affords the NH-aziridines in good yield. Using transfer hydrogenation conditions, the NH-aziridines were regioselectively opened to the corresponding enantiopure alpha-amino phosphonates without N-activation and in excellent yield.     

Reaction of magnesium alkylidene carbenoids with lithium alpha-sulfonyl carbanions: a novel synthesis of tri- and tetra-substituted allenes from 1-chlorovinyl p-tolyl sulfoxides and sulfones

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from ketones and chloromethyl p-tolyl sulfoxide, with ethylmagnesium chloride or isopropylmagnesium chloride at below -78 degrees C gave magnesium alkylidene carbenoids in about 90% yields. The reaction of the generated carbenoids with lithium alpha-sulfonyl carbanions was found to afford tri- and tetra-substituted allenes. Both cyclic ketones and acyclic ketones were useful in this procedure. However, the 1-chlorovinyl p-tolyl sulfoxides derived from aldehydes gave only rearranged products, acetylenes, under the reaction conditions. The magnesium alkylidene carbenoid derived from an optically active 1-chlorovinyl p-tolyl sulfoxide was treated with lithium alpha-carbanion of 1-naphthyl phenyl sulfone; however, the obtained allene was found to be racemic. The mechanism of this reaction is also discussed.     

Dynamic kinetic transformation of sulfinyl chlorides: synthesis of enantiomerically pure C(2)-symmetric bis-sulfoxides.

Two modular and highly convergent approaches for the synthesis of both isomers of a large number of optically pure C(2)-symmetric bis-sulfoxides have been developed, and their scope and limitations have been assessed. The first one uses as intermediate diastereomerically pure C(2)-symmetric bis-sulfinate esters 6(S(S),S(S)) and 6(R(S),R(S)), obtained by dynamic kinetic resolution of ethane-1,2-bis-sulfinyl chloride 5. A single inducer of chirality, the glucose-derived DAG (diacetone-D-glucose) 1 is used for the enantioselective synthesis of both diastereomerically pure C(2)-symmetric bis-sulfinate esters, thanks to the opposite stereodirecting effect of pyridine and (i)Pr(2)NEt used to catalyze the reaction. The second approach is based on the copper-catalyzed oxidative coupling of optically pure lithiomethyl sulfoxides. Both isomers of a large number of methyl sulfoxides can be obtained in a convergent manner using (R(S))- and (S(S))-DAG methanesulfinate esters 8R(S) and 8S(S). Methanesulfinates 8R(S) and 8S(S) are also obtained in an enantioselective way by a dynamic kinetic resolution of methane sulfinyl chloride 24. The final bis-sulfoxides are obtained with enhanced enantioselectivities compared to the corresponding monomers, as a result of the Horeau effect which is operating in both approaches. A model based on the formation of pentacoordinated sulfur intermediate is proposed. This model can explain the dynamic kinetic resolution observed via Berry pseudorotations, without the commonly accepted in situ racemization of the starting material. The usefulness of the approaches is demonstrated by the preparation of complexes of Pd(II) and Ru(II) bearing bidentated chiral sulfoxides as ligands.     

α-phosphoryl sulfoxides. X. A general synthesis of optically active α-chlorovinyl sulfoxides

A general and efficient synthesis of enantiomeric α-chlorovinyl p-tolyl sulfoxides 1 using (+)-(S)_C(S)_S-α-chloro-α-dimethoxyphosphorylmethyl p-tolyl sulfoxide as a key substrate for the Horner-Wittig reaction with carbonyl compounds is described. The ratio of geometrical isomers of 1 was determined and briefly investigated. The X-ray diffraction structures of (Z)-1-chloro-1-p-tolylsulfinyl-2-phenyl-ethene and (Z)-1-chloro-1-p-tolylsulfinyl-2-(2-thienyl)-ethene are reported.     

Stereoselective formation of glycosyl sulfoxides and their subsequent equilibration: ring inversion of an alpha-xylopyranosyl sulfoxide dependent on the configuration at sulfur

A series of four S-allyl D-thiopyranosides, alpha- and beta-manno and xylo, were oxidized with MCPBA at low temperature to give seven of the eight possible sulfoxides, whose configuration at sulfur was determined either directly by X-ray crystallography or by correlation with closely related structures. For the axial thioglycosides oxidation leads very predominantly to the (R)(S)-diastereomer in the xylo series and exclusively so in the manno series; the configuration at C2 is of little importance in determining the stereoselectivity of oxidation of axial thioglycopyranosides. In the equatorial series the configuration at C2 has a significant effect on the outcome of the reaction as, although both series favored the (S)(S)-sulfoxide, selectivity was significantly higher in the case of the beta-mannoside than of the beta-xyloside. The two alpha-xylo sulfoxides have different conformations of the pyranoside ring with the (R)(S)-isomer adopting the (1)C(4) chair and the (S)(S)-diastereomer the (4)C(1). Each pair of diastereomeric sulfoxides was thermally equilibrated in C(6)D(6) and in CD(3)OD. In the mannose series the kinetic isomers are also thermodynamically preferred. In the xylose series, on the other hand, the nature of the thermodynamic isomer in both the alpha- and beta-anomers is a function of solvent with a switch observed on going from C(6)D(6) to CD(3)OD. The results are rationalized in terms of the exo-anomeric effect, steric shielding provided by H3 and H5 in the axial series, the interaction of the C2-O2 and sulfoxide dipoles, and increased steric interactions on hydrogen bonding of the sulfoxides to CD(3)OD.     

Synthesis of enantiomerically pure (S)-methanocarbaribo uracil nucleoside derivatives for use as antiviral agents and P2Y receptor ligands

We have developed an approach toward enantiomerically pure (S)-methanocarba ribonucleosides based on several functional group transformations on a sensitive bicyclo[3.1.0]hexane system. D-ribose was transformed into methanocarba alcohol 3 followed by conversion of the OH group to a nitrile with inversion of configuration at C4. The nitrile group was subsequently reduced in two stages to the 5'-hydroxymethyl group. An ester group appended to a tertiary carbon (C1) was transformed to an amino group as a nucleobase precursor.     

Applications of the sulfinimine-mediated asymmetric strecker synthesis to the synthesis of alpha-alkyl alpha-amino acids

Addition of Et(2)AlCN and i-PrOH to ketosulfinimines (N-sulfinyl imines) affords corresponding alpha-alkyl alpha-amino nitriles in moderate to good yields. The diastereoselectivity is largely dependent on the E/Z isomer ratio of the ketosulfinimine. Hydrolysis of the diastereomerically pure amino nitriles affords enantiopure alpha-alkyl alpha-amino acids in moderate to good yields.     

Sulfoxide-controlled S(N)2' displacements between cyanocuprates and epoxy vinyl sulfoxides

Two short and convergent routes have been devised for the preparation of enantiomerically pure acyclic epoxy vinyl sulfoxides. These substrates undergo highly regio- and stereoselective S(N)2' displacements with lithium cyanocuprates to give alpha'-alkylated, gamma-oxygenated Z alpha,beta-unsaturated sulfoxides in moderate to good yields and with good to excellent diastereoselectivities. The absolute configuration of the newly formed carbon-carbon bond is primarily controlled by the chiral sulfur atom, which in a nonreinforcing situation can override the intrinsic anti tendency of the vinyl oxirane moiety and forces the cuprate to undergo syn addition. The hydroxy vinyl sulfoxide functionality of the resulting adducts should allow for subsequent asymmetric transformations thus enhancing the synthetic usefulness of this methodology.     

Stereospecific Pd(0)-catalyzed arylation of an allylic hydroxy phosphonate derivative: formal synthesis of (S)-(+)-ar-turmerone

Reaction of the (1S)-allylic hydroxy phosphonate 1(S) with methyl chloroformate in pyridine yields the corresponding carbonate 3(S). The carbonate 3(S) undergoes a palladium-catalyzed arylation with p-tolyl tributylstannane to give both the 1E and 1Z vinyl phosphonates 6 (85:15). The E and Z vinyl phosphonates 6 were shown to have the opposite configuration at C-3. The major vinyl phosphonate isomer (3S,1E), was converted to (3S)-3-(p-tolyl)-butanal 8(S), completing a formal total synthesis of (S)-ar-turmerone 5a.     

Sulfenic acids in the carbohydrate field. Synthesis of transient glycosulfenic acids and their addition to unsaturated acceptors

A new method is described for building up anomeric glycosyl sulfoxides, via the formation of transient glycosulfenic acids and their addition to unsaturated acceptors. Thermolysis of alpha- and beta-3-[(2,3,4,6-tetra-O-acetyl-D-glucopyranosyl)sulfinyl]propanenitriles affords 1-glucosulfenic acids, which are reacted in situ with common substituted alkynes. The obtained (R(S),E)-2-[(2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl)sulfinyl]-2-butendioates are involved as enantiopure sulfinyl dienophiles in Diels-Alder reactions with 2,3-dimethyl-1,3-butadiene to evaluate the role that the sugar moiety plays in the steric control of the cycloaddition. This chemistry provides a direct synthetic strategy for the stereocontrolled connection between thioglycon and aglycon moieties, thus offering the basis for an easy elaboration of new molecules incorporating thiosugar residues.     

Relative Stabilities of Transition States Determine Diastereocontrol in Sulfur Ylide Additions onto Chiral N-Sulfinyl Imines

Additions of methylphenylsulfonium methylide onto chiral non-racemic N-sulfinyl imines (R'-SO-N=CH-R, R'=t-butyl, R=protected diol), followed by ring closure, yield terminal aziridines with high diastereoselectivity. Control reactions have established that both N- and C- iminyl substituents impact product preference, and when properly matched, one addition product is selected almost exclusively. Using solution-phase density functional computational methods, minima and transition state searches have been performed to reveal the structural origins of the diastereoselectivity. Our computational findings indicate that ring closure is fast and irreversible, and consequently, the relative energies of the transition states for the competing Re/Si addition steps determine the product diastereomeric ratios. Analysis of addition transition state structures reveals the causes of selectivity as arising from the N- and C- iminyl substituents, and we identify the S (R) configuration of the N-sulfinyl sulfur atom as the dominant director of Si (Re) addition. The control attributed to the sulfur configuration is tied to an important favorable internal interaction between the sulfinyl oxygen and the iminyl hydrogen. The protected diol acts as a secondary director, owing to steric/electrostatic interactions with the approaching ylide.     

Asymmetric synthesis of (S)-(-)-xylopinine. Use of the sulfinyl group as an ipso director in aromatic SE

Optically pure (S)-(-)-xylopinine 2 was prepared in three steps in 52% overall yield. Thus, condensation of the carbanion derived from (S)-4 with the (S)-(E)-sulfinylimine 5 gave a 2:1 mixture of tetrahydroisoquinolines 6a and 6b, differing only in configuration at sulfur. N-Desulfinylation of this mixture gave the diastereomeric sulfoxides which, without separation, were converted into (S)-(-)-xylopinine (2) with loss of the sulfinyl moieties under Pictet-Spengler conditions. This unprecedented ipso electrophilic substitution of a sulfinyl group may have synthetic implications beyond that described in this work.