Diastereoselective Alkylation Research Articles

Stereoselective syntheses of (+)-α- and (−)-β-conhydrine from L-aspartic acid

An efficient synthesis of (+)-α-conhydrine 1 and (−)-β-conhydrine 2 has been achieved by diastereoselective alkylation of an amino aldehyde derivative 7 with ethylmagnesium bromide or diethylzinc.

Cyclic Nitriles: Diastereoselective Alkylations

[reaction: see text] Diastereoselective alkylations of metalated conformationally locked 4-tert-butylcyclohexanecarbonitrile are highly diastereoselective with magnesium and copper counterions but only modestly diastereoselective with lithium as the counterion. Selective generation of diverse metalated nitriles is readily achieved through bromine-magnesium, -copper, and -lithium exchange reactions of the corresponding bromonitrile or, for lithium, by deprotonating the parent nitrile with lithium diethylamide. Collectively, high alkylation stereoselectivities correlate with the retentive alkylations of C-metalated nitriles, whereas N-lithiated nitriles alkylate with modest selectivity, reflecting minimal steric differences in the corresponding axial and equatorial electrophile trajectories.

Diastereoselective Alkylation of (Arene)tricarbonylchromium and Ferrocene Complexes Using a Chiral, C2‐Symmetrical 1,2‐Diamine as Auxiliary

AbstractThe aminal of (benzaldehyde)tricarbonylchromium and en‐antiopure bipyrrolidine undergoes diastereoselective ortho‐metallation with butyllithium. Quenching with various electrophiles, followed by hydrolysis of the aminal, affords ortho‐substituted (benzaldehyde)tricarbonylchromium compounds with high ee (91–99 %). When quenched with Ph2PCl, a new chiral P,N‐bidentate ligand is obtained, which shows efficiency in Pd‐ and Cu‐catalysed reactions. The aminal of ferrocenecarbaldehyde could also be formed, but the ortho‐deprotonation occurs with only moderate diastereoselectivity (70 %). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

An Efficient Asymmetric Synthesis of 2‐Substituted 1,4‐Benzodiazepin‐3‐one as a Potential Molecular Scaffold

Abstract2‐Substituted 1,4‐benzodiazepine‐2‐one compounds (9–12) were obtained by a highly diastereoselective alkylation of a seven‐membered ring benzolactam (8) in the presence of (R)‐phenylglycinol as a chiral inductor. The corresponding acid derivative (16) afforded a conformationally constrained structure suitable for preparing peptidomimetic analogues useful as a novel molecular scaffold. After cleavage of the chiral appendage this approach might also lead efficiently to enantiomerically pure 2‐substituted benzodiazepines (15). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Reversible Enolization of β-Amino Carboxamides by Lithium Hexamethyldisilazide

The enolization of beta-amino carboxamides by lithium hexamethyldisilazide (LiHMDS) in THF/toluene and subsequent diastereoselective alkylation with CH(3)I are reported. In situ IR spectroscopic studies reveal that beta-amino carboxamides coordinate to LiHMDS at -78 degrees C before enolization. Comparison with structurally similar carboxamides suggests that the beta-amino group promotes the enolization. IR spectroscopic studies also show that the enolization is reversible. Efficient trapping of the enolate by CH(3)I affords full conversion to products. (6)Li and (15)N NMR spectroscopic studies reveal that lithium enolate-LiHMDS mixed dimers and trimers as well as a homoaggregated enolate are formed during the reaction. At ambient temperature, racemization of the beta-position through a putative reversible Michael addition was observed.

Hetero‐Diels—Alder and Pyroglutamate Approaches to (2S,4R)‐2‐Methylamino‐5‐hydroxy‐4‐methylpentanoic Acid.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereoselective Synthesis of (+)‐Lauthisan.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of a Ceramide Sphingolipid as a Potential Sex Pheromone of the Hair CrabErimacrus isenbeckiiUsing Butane-2,3-diacetal Desymmetrised Glycolic Acid Building Blocks

A stereoselective synthesis of a ceramide sphingolipid as a potential sex pheromone of the hair crab Erimacrus isenbeckii is reported using diastereoselective alkylation and aldol reactions of butane-2,3-diacetal (BDA) desymmetrised glycolic acid building blocks as the key synthetic steps.

Enantioselective Total Synthesis of Enokipodins A–D, Antimicrobial Sesquiterpenes Produced by the Mushroom, Flammulina velutipes

The first enantioselective total synthesis of enokipodins A, B, C and D, highly oxidized alpha-cuparenone-type sesquiterpenoids possessing antimicrobial activity, was accomplished in 8-28% overall yields from methyl (2,5-dimethoxy-4-methylphenyl)acetate by applying Meyers' diastereoselective alkylation protocol for the construction of their C7-quaternary asymmetric center. The present synthesis confirmed the absolute configuration of the enokipodins, and also constitutes a formal enantioselective synthesis of (S)-1,4-cuparenediol and (S)-cuparene-1,4-quinone.

Total synthesis of 12,13-desoxyepothilone B (Epothilone D)

A highly convergent total synthesis of 12,13-desoxyepothilone B ( 4, Epothilone D) is described involving the coupling of vinyl iodide ( 5) and olefin ( 6). Key steps in the synthesis are the introduction of chirality at C15 via highly enantioselective lipase-mediated enzymatic resolution, diastereoselective alkylation at C8, highly diastereoselective Evans aldol reaction to establish C6–C7, and Mukaiyama aldol reaction to introduce chiral center C3. Palladium catalyzed Suzuki coupling of ( 5) and ( 6) provided the methyl ester ( 27), which was converted to 12,13-desoxyepothilone B ( 4).

Diastereoselective Alkylation of β-Amino Esters: Structural and Rate Studies Reveal Alkylations of Hexameric Lithium Enolates

Alkylation of beta-amino ester enolates proceeds with high diastereoselectivity. Single crystal, powder, and solution X-ray diffraction studies of the enolate show that the racemic enolate forms prismatic hexamers. 6Li NMR spectroscopic studies on partially racemic enolates reveal complex mixtures of homo- and heterochiral hexamers. An implicit fit of the aggregate populations to the Boltzmann distribution provides the free energy differences and equilibrium constants for the ensemble. Rate studies show that enolate alkylation occurs directly from the hexamer with participation by THF. A mechanism based on the alkylation of a ladder-like aggregate is proposed.

Stereoselective Synthesis of (-)-Centrolobine

The stereoselective synthesis of (� )-centrolobine has been accomplished starting from D-glyceraldehyde acetonide by a combination of chelation-controlled diastereoselective alkylation and ring-closing metathesis. A high degree of 1,3-asymmetric induction has been realized in an ether system.

How We Drifted into Peptide Chemistry and Where We Have Arrived at

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective Total Synthesis of Enokipodins A—D.

Abstract The first enantioselective total synthesis of enokipodins A–D, highly oxidized α-cuparenone-type sesquiterpenoids with antimicrobial activity, was accomplished by using Meyers' diastereoselective alkylation protocol for the construction of the C7-quaternary asymmetric center. The present synthesis also constitutes a formal enantioselective synthesis of ( S )-1,4-cuparenediol and ( S )-cuparene-1,4-quinone.

Hetero-Diels–Alder and pyroglutamate approaches to (2 S,4 R)-2-methylamino-5-hydroxy-4-methylpentanoic acid

The stereoselective syntheses of fully protected (2 S,4 R)-2-methylamino-5-hydroxy-4-methylpentanoic acid, a non-coded amino acid of cyclomarin A, and its diastereomer are reported. A pyroglutamate template was employed in the key diastereoselective alkylation used for introducing the 4-methyl stereochemistry. In addition, the first diastereoselective intramolecular hetero-Diels–Alder of a 2-cyano-1-azadiene with an electron deficient dienophile is described.

Stereoselective synthesis of (+)-lauthisan

Stereoselective synthesis of (+)-lauthisan has been accomplished starting from d-glyceraldehyde acetonide by combination of diastereoselective alkylation and ring-closing metathesis. High degree of 1,3-asymmetric induction has been realized in ether system.

Highly Diastereoselective Alkylation of Vicinal Dianions of Chiral Succinic Acid Derivatives: A New General Strategy to (R)‐β‐Arylmethl‐γ‐butyrolactones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

How we drifted into peptide chemistry and where we have arrived at

The history of peptide chemistry in our group is described. It all started with the cyclic undecapeptide cyclosporin, the immunosuppressive compound, which is commercialised as Sandimmune ®/Neoral ® by Sandoz/Novartis, and which has revolutionized transplant medicine. The discovery that cyclosporin can be deprotonated to a hexalithio derivative, and thus C-alkylated on a sarcosine moiety, led us into a research project on peptide modifications. We defined structural prerequisites for the use of peptide enolates and for electrolytic decarboxylation of peptides. Parallel to these activities, the group was engaged in developing synthetic methodologies aimed at stereoselective preparations of α-, β-, and γ-amino acid derivatives (cf. diastereoselective alkylations, self regeneration of stereogenic centers, axially chiral enolates). A third avenue into peptide chemistry originated from our investigations on the biopolymer PHB (poly-3-hydroxybutanoic acid); the question arose ‘what happens upon replacement of chain-bound O by NH in the polyester?’ A brief summary is given of the results obtained in our ensuing discovery tour of β-peptides built of homologated proteinogenic amino acids. They form secondary structures with short chain lengths and they have unexpected physiological properties, rendering them candidates for peptidic drugs. The synthesis of β 3-peptides is straightforward, and in the meantime most of the Fmoc-protected building blocks are commercial. The β 2-homoamino acids are less readily available. Their preparation and the assembly of a β 2-eicosapeptide with the twenty proteinogenic side chains are discussed herein. The reasons for the chosen sequence and the strategy of what turned out to be a 159-step synthesis are described. Full experimental details are given for the preparation of the dimeric Fmoc-β 2hXaa(PG)-β 2hXaa(PG)-OH building blocks used, for their solid-phase coupling to two β 2-decapeptide segments, for the thioligation, and for the purification, isolation and spectroscopic characterization of the resulting 20mer. An outlook to future projects in the exciting field of β- and γ-peptide chemistry and biology is given.

Total Synthesis and Structural Revision of (+)‐Amphidinolide W.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective total synthesis of enokipodins A–D

The first enantioselective total synthesis of enokipodins A–D, highly oxidized α-cuparenone-type sesquiterpenoids with antimicrobial activity, was accomplished by using Meyers' diastereoselective alkylation protocol for the construction of the C7-quaternary asymmetric center. The present synthesis also constitutes a formal enantioselective synthesis of ( S)-1,4-cuparenediol and ( S)-cuparene-1,4-quinone.