Chiral Sulfinimines Research Articles

Asymmetric Synthesis of Structurally Diverse Aminophosphonic Acids by Using Enantiopure N‐(p‐Tolylsulfinyl)cinnamaldimines as Reagents

AbstractWe have developed new approaches to diverse enantiopure aminophosphonic acids by using enantiomeric (S)‐N‐(p‐tolylsulfinyl)cinnamaldimine (1) as a single starting material. The synthetic strategy is based on a highly diastereoselective addition reaction of phosphite anion or α‐phosphonate carbanion to a sulfinimine followed by isolation of the major diastereoisomeric α‐amino‐ or β‐amino adducts and their further conversion to the desired targets through proper transformation of the cinnamylidene moiety. Both diastereoisomerically pure (SS,RC)‐ and (SS,SC)‐α‐amino adducts 2 and 4 obtained were converted under acidic conditions into the unknown enantiomerically pure (R)‐ and (S)‐α‐amino‐β,γ‐propenylphosphonic acids 3. In the same way, the enantiopure (R)‐ and (S)‐β‐amino‐γ,δ‐butenylphosphonic acids were synthesized from the corresponding (SS,RC)‐ and (SS,SC)‐β‐amino adducts. Starting from the (SS,RC)‐β‐amino adduct a new stereoselective synthesis of (R)‐2‐amino‐3‐phosphonopropanoic acid (9) has been accomplished in three simple steps (tandem ozonolysis/reduction reaction, oxidation reaction and acidic hydrolysis) in an overall 40 % yield. The 3‐amino regioisomer of 9 has been prepared from the (SS,RC)‐α‐amino adduct 2 through a two‐reaction sequence involving a tandem ozonolysis/reduction reaction and a Mitsunobu cyanation/acidic hydrolysis. The overall yield of this conversion to 11 was 52.5 %. According to our strategy, we have been able to complete the first synthesis of the enantiopure (R)‐phosphoemeriamine 15, which is an unknown phosphonic analogue of emeriamine (aminocarnitine). The conversion of the (SS,RC)‐β‐amino adduct 5 into (R)‐phosphoemeriamine has been accomplished in five simple synthetic steps (ozonolysis/reduction reaction, mesylation reaction, amination reaction, methylation reaction and acidic hydrolysis) in 24 % overall yield. The stereochemistry of the addition of PIII‐nucleophiles and α‐phosphonate carbanion to a chiral sulfinimine is also discussed.

ChemInform Abstract: An Approach to the Stereoselective Synthesis of Enantiopure Dihydropyrroles and Aziridines from a Common Sulfinyl‐Sulfinamide Intermediate.

AbstractAddition of chiral sulfinimines to vinylic sulfoxides results in stereoselective formation of the synthetic intermediates (III).

On chirality transfer in electron donor-acceptor complexes. A prediction for the sulfinimine···BF3 system

Stabilization energies of the electron donor-acceptor sulfinimine···BF(3) complexes calculated at either the B3LYP/aug-cc-pVTZ or the MP2/aug-cc-pVTZ level do not allow to judge, whether the N- or O-atom in sulfinimine is stronger electron-donor to BF(3) . The problem seems to be solvable because chirality transfer phenomenon between chiral sulfinimine and achiral BF(3) is expected to be vibrational circular dichroism (VCD) active. Moreover, the bands associated with the achiral BF(3) molecule are predicted to be the most intense in the entire spectrum. However, the VCD band robustness analyses show that most of the chirality transfer modes of BF(3) are unreliable. Conversely, variation of VCD intensity with change of intermolecular distance, angle, and selected dihedrals between the complex partners shows that to establish the robustness of chirality transfer mode. It is also necessary to determine the influence of the potential energy surface (PES) shape on the VCD intensity. At the moment, there is still no universal criterion for the chirality transfer mode robustness and the conclusions formulated based on one system cannot be directly transferred even to a quite similar one. However, it is certain that more attention should be focused on relation of PES shape and the VCD mode robustness problem.

Multicomponent Synthesis of Chiral Sulfinimines

Two oxathiozolidine-S-oxide templates have been developed and used in a four-component coupling protocol for the synthesis of a wide range of chiral sulfinimines in high enantiomeric excesses. The templates can be synthesized from cheap commodity chemicals in three steps in high yields. Furthermore the template is easily recovered in high yields for recycling.

Reductive Lithiation of Methyl Substituted Diarylmethylsilanes: Application to Silanediol Peptide Precursors

Reductive lithiation of methyl-substituted diarylmethylsilanes using lithium naphthalenide represents a practical method for the preparation of the corresponding silyl lithium reagents. Their addition to chiral sulfinimines affords versatile precursors to silanols and silanediols. The replacement of the currently used diphenylsilane motif by a more labile diarylsilane moiety allows the selective hydrolysis of one or two aryl groups by treatment with TFA.

ChemInform Abstract: Trifluoroacetaldehyde: A Useful Industrial Bulk Material for the Synthesis of Trifluoromethylated Amino Compounds.

AbstractThe application of the title compound for the synthesis of trifluoromethylated amino compounds via reductive amination reactions, and in the synthesis of chiral α‐substituted trifluoroethylamino compounds via chiral sulfinimine (X) is reported.

ChemInform Abstract: Asymmetric Aziridination by Reaction of Chiral Sulfinimine Derived from (+)-Camphor with Dimethyloxosulfonium Methylide.

Abstract Addition of dimethyloxosulfonium methylide to chiral nonracemic pure (+)-camphor-derived sulfinimine I affords N-sulfinyl aziridine. which are easily separated The N-(+)-camphor-based-sulfinyl auxiliary was removed without ring opening by treatment with MeLi.

Asymmetric Synthesis of 2-Alkyl-Substituted 2,5-Dihydropyrroles from Optically Active Aza-Baylis−Hillman Adducts. Formal Synthesis of (−)-Trachelanthamidine.

A series of optically active 2-alkyl-substituted 2,5-dihydropyrroles were prepared via the asymmetric aza-Baylis-Hillman equivalent reaction and subsequent ring-closure metathesis reaction. Optically active aza-Baylis-Hillman adducts underwent a smooth two-step conversion to N-allyl-beta-amino-alpha-methylene esters in high yield, which gave chiral 2,5-dihydropyrroles, potential precursors for the aza-heterocyclic synthesis, almost quantitatively through RCM reaction catalyzed by Grubbs catalyst. The conversion was carried out without loss of the optical purity of the starting material. Synthetic application of the method to (-)-trachelanthamidine was examined. Hydrogenation of 2,5-dihydropyrrole took place smoothly to give the corresponding 2,3-disubstituted pyrrolidine in good yield. The stereoselectivity of the hydrogenation was sensitive to the presence or absence of the protective group in the C2-side chain. The TBS-protected 2,5-dihydropyrrole gave a 1:1 mixture of the cis/trans isomers, while free alcohol afforded the trans-2,3-disubstituted pyrrolidine in a selectivity of 6:1. The formal synthesis of (-)-trachelanthamidine was achieved in 11 steps from a chiral sulfinimine. This methodology provided a convenient procedure for the preparation of C2-alkyl-substituted 2,5-dihydropyroles with retention of high optical purity.

Further Studies toward the Stereocontrolled Synthesis of Silicon-Containing Peptide Mimics

Further studies are reported on the utilization of the versatile reaction between chiral sulfinimines and alkyldiphenylsilyl lithium reagents with the goal of preparing a wide range of silanediol-based protease inhibitors. In particular, focus has been placed to demonstrate how a number of genetically encoded amino acid side chains such as serine, threonine, tyrosine, lysine, proline, arginine, aspartate and asparagine might be incorporated into the overall approach. Efforts to apply this synthetic methodology for accessing biologically relevant silanediol dipeptide mimics are also described. This includes the synthesis of a potential inhibitor of the human neutrophil elastase, as well as a diphenylsilane mimic of a hexapeptide fragment of the human islet amyloid polypeptide.

Total Synthesis of Siomycin A: Construction of Synthetic Segments

The five practical segments for the total synthesis of siomycin A, that is, the dehydropiperidine segment A (5), the pentapeptide segment B (3), the dihydroquinoline segment C (6), and the beta-phenylselenoalanine dipeptide segments D (7) and E (4), were synthesized. Segment A (5) was constructed by the coupling of the azomethine ylide and the chiral sulfinimine, followed by the stereoselective reduction of the six-membered imine function. Segment B (3) was synthesized by the phenylselenylation of the beta-lactone, stereoselective vinylzinc addition to the chiral sulfinimine, and oxazoline-thioamide conversion. Segment C (6) was prepared by the one-pot olefination of the tetrahydroquinoline N-oxide using triflic anhydride and triethylamine, stereoselective reduction of the methyl ketone function, and regioselective Yb(OTf)(3)-catalyzed epoxide opening by the amino group. Segments D (7) and E (4) were synthesized by coupling of the properly protected beta-phenylselenoalanines.

Stereoselective Synthesis of Novel Uracil Polyoxin C Conjugates as Substrate Analogues of Chitin Synthase

Stereoselective syntheses of both the natural (C5'- S) and unnatural (C5'- R) diastereoisomers of uracil polyoxin C methyl ester have been developed. The key stereocontrolled step involves nucleophilic addition of trimethylsilyl cyanide to the appropriate chiral sulfinimine derived from 2',3'-protected 5'-formyluridine and (S)-(-)-tert-butanesulfinamide or (R)-(+)-tert-butanesulfinamide, respectively. A variety of substrate mimics designed to function as inhibitors of chitin synthase have been synthesized by conjugation of the methyl ester of uracil polyoxin C (UPOC) with activated isoxazole carboxylic acids. Amide bond formation was accomplished via coupling of the amino functionality of UPOC methyl ester with a free isoxazole acid using HBTU or alternatively an isoxazole pentafluorophenyl ester. The substrate mimics incorporate features of the nucleoside-peptide antibiotics, the polyoxins and the nikkomycins, as well as features of the transition state structure expected during polymerization of the natural chitin synthase substrate uridine diphosphoryl-N-acetylglucosamine (UDP-GlcNAc), namely, a metal-binding site and glycosyl oxocarbenium ion mimic.

Rapid Assembly of the Polyhydroxylated β-Amino Acid Constituents of Microsclerodermins C, D, and E

A very short and efficient synthesis of protected derivatives of APTO and AETD, the complex polyhydroxylated beta-amino acid residues present in microsclerodermins C, D, and E, is described. The targets are obtained in only five steps, in 23% and 16% overall yields, respectively. The key transformation involves the completely diastereoselective two-carbon homologation of appropriately selected intermediate chiral sulfinimines.

Convenient synthesis of chiral non-racemic S-mesityl sulfinimines

A direct multi-component coupling of (2 S,4 R,5 S)- N-tosyl-4-methyl-5-phenyl-1,2,3-oxathiozolidine-2-oxide with mesityl magnesium bromide, LHMDS and a range of aldehydes produces chiral sulfinimines in essentially optically pure form in an operationally simple single pot procedure.

Stereocontrolled Synthesis of Methyl Silanediol Peptide Mimics

The treatment of chiral sulfinimines with (methyldiphenylsilyl)lithium gives alpha-(methyldiphenylsilyl)sulfinamides with excellent diastereoselectivity, and in good yield. The presence of alpha-protons on the imines is also well tolerated. The sulfinamide auxiliary is easily removed via treatment with methanolic HCl and the resulting amine extended into peptide chains accordingly. The diphenylsilyl moiety is a resilient protecting group for the corresponding silanediol, which can be unmasked via treatment with TfOH, followed by aqueous hydrolysis. The crude silanediol may be isolated and purified as its corresponding bis-TMS siloxane via protection with TMSCl, and converted back to the desired silanediol via hydrolysis with aqueous KOH. Efforts to apply this approach to biologically relevant silanediol peptide mimics, with a view to protease inhibition, are described.

Enantioselective Total Synthesis of (+)-Jasplakinolide

An enantioselective total synthesis of (+)-jasplakinolide is described. The synthesis of the polyketide template utilized a diastereoselective syn-aldol, ortho-ester Claisen rearrangement followed by efficient conversion to a cyanide. The beta-amino acid unit was constructed in a highly diastereoselective manner utilizing nucleophilic addition to a chiral sulfinimine. Yamaguchi macrocyclization and removal of the protecting group provided a convenient access to (+)-jasplakinolide.

Asymmetric Aza-Mannich Reactions of Sulfinimines: Scope and Application to the Total Synthesis of a Bromopyrrole Alkaloid

[reaction: see text] An asymmetric intermolecular aza variant of the Mannich reaction is reported utilizing chiral sulfinimine anions as the nucleophile and N-sulfonyl aldimines as the electrophilic component. A wide range of nucleophiles and electrophiles are tolerated by the reaction conditions, delivering the condensation products in good to excellent yield with a high degree of stereocontrol. Application of this methodology to the total synthesis of a natural product is reported.

Lewis Base‐Catalyzed Diastereoselective Mannich‐Type Reaction Between Ketene Silyl Acetals and Chiral Sulfinimines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Room‐Temperature Protocol for the Rhodium(I)‐Catalyzed Addition of Arylboron Compounds to Sulfinimines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Lewis Base Catalyzed Diastereoselective Strecker‐Type Reaction Between Trimethylsilyl Cyanide and Chiral Sulfinimines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Mannich-type Reaction of Methylene Active Compounds with a Chiral Sulfinimine of Trifluoropyruvate: New Highly Stereoselective Synthesis of (S)-α-Trifluoromethyl-Aspartic Acid

A strongly improved, highly stereoselective synthesis of (S)-α-trifluoromethyl aspartic acid via addition of lithium malonate to a chiral sulfinimine of trifluoropyruvate is presented. Keywords: fluorine, sulfinimines, mannich-reaction, trifluoromethyl amino acids, stereoselective synthesis