Vinylmagnesium Bromide Research Articles

Stereoselective approach to aminocyclopentitols from Garner aldehydes

An efficient stereoselective synthesis of aminocyclopentitols from (S)- and (R)-Garner aldehydes is presented here. The key steps involved diastereoselective addition of vinylmagnesium bromide to a Garner aldehyde, ring closing metathesis, diastereoselective dihydroxylation and stereoselective reduction of the keto functionality.

ChemInform Abstract: Selective “One‐Pot” Synthesis of Functionalized Cyclopentenones.

AbstractReaction of squaric acid derivatives with vinyl magnesium bromide followed by treatment with trifluoroethanol allows a new and stereoselective access to functionalized cyclopentenones of type (III)/ (V).

Synthesis of Protected 2-Pyrrolylalanine for Peptide Chemistry and Examination of Its Influence on Prolyl Amide Isomer Equilibrium

Protected enantiopure 2-pyrrolylalanine was synthesized for application in peptide science as an electron-rich arylalanine (histidine) analog with π-donor capability. (2S)-N-(Boc)-N'-(Phenylsulfonyl)-, (2S)-N,N'-bis-(phenylsulfonyl)-, and (2S)-N,N'-bis-(Boc)-3-(2-pyrrolyl)alanines (10, 3, and 14, respectively) were made in 13-17% overall yields and six to seven steps from oxazolidine β-methyl ester 4. Homoallylic ketone 5 was prepared by a copper-catalyzed cascade addition of vinylmagnesium bromide to ester 4 and converted to pyrrolyl amino alcohol 7 by olefin oxidation and Paal-Knorr condensation. Protecting group shuffle and oxidation of the primary alcohol enabled the synthesis of pyrrolylalanines. The bis-Boc analog 14 proved useful in peptide chemistry and was employed to make N-acetyl-pyrrolylalaninyl-proline N''-methylamide 25. A study of the influence of the pyrrole moiety on the prolyl amide isomer equilibrium of 25 using (1)H NMR spectroscopy in chloroform, DMSO, and water demonstrated that the pyrrolylalanine peptide exhibited behavior and conformations different from those of other arylalanine analogs.

Selective “One-Pot” Synthesis of Functionalized Cyclopentenones

Double addition (1,2-1,4) of vinyl magnesium bromide to squaric acid derivatives allows the preparation of polyoxygenated cyclopentenones (8) in a "one-pot" procedure. The reaction occurs through the intermediate formation of octatetraenes (6). Protonation of this latter intermediate at -78 °C with TFE occurs selectively at the vinyl CH(2) closer to the metallic centers. DFT studies of the cyclization step justify the observed diastereoselectivity.

Design, Synthesis, and Biological Evaluation of Novel Fluorinated Ethanolamines

The preparation of novel fluorinated allylamines and their use as key fragments for the stereoselective synthesis of hydroxyethyl secondary amine (HEA)-type peptidomimetics is described. Our strategy employs chiral sulfinyl imines as synthesis intermediates, by treatment of hemiaminal precursors with two equivalents of vinylmagnesium bromide. The subsequent oxidation of the allylic amines to the corresponding epoxides was achieved by treatment with methyl(trifluoromethyl)dioxirane. Finally, epoxide ring opening with a range of nitrogen nucleophiles provided a library of HEA-derived peptidomimetics with a phenyldifluoromethylene moiety. The biological evaluation of these derivatives revealed compounds with remarkable BACE1 inhibitory activity. Docking studies revealed the influence of the fluorine atoms in the binding mode of the synthesized ligands. Furthermore, the biological evaluation of our final products and synthesis intermediates led to the discovery of compounds with antimicrobial activity against Mycobacterium and Nocardia species.

Toward the Total Synthesis of Bryostatin 11: Stereoselective Construction of the C13-Exocyclic Enoate in the C1–C16 Fragment

We have utilized a spiroketal template in an approach to the C1–C16 fragment of bryostatin. The stereoselective construction of an exocyclic enoate at C13 and insertion of a vinyl group on C15 were accomplished by using Peterson–Yamamoto olefination and copper-catalyzed addition of vinyl magnesium bromide, respectively.

ChemInform Abstract: Synthesis of 3‐Aryl‐3‐pyrrolines and 3‐Arylpyrroles via Spontaneous Rearrangement of N‐Sulfinyl 2‐Aryl‐2‐vinylaziridines.

AbstractThe addition of vinylmagnesium bromide to ketimines (I) forms intermediate 2‐aryl‐2‐vinylaziridines which spontaneously rearrange to 3‐pyrrolines (III).

Enantioselective Synthesis of (–)‐Methoxyestrone

AbstractEnantioselective synthesis of unnatural (–)‐methoxyestrone in 12 steps from the commercially available tetralone based on the formation of a chiral bicyclic intermediate having the A–B steroid ring framework was accomplished. The crucial synthetic step comprised the enantioselective conjugate addition of vinylmagnesium bromide to a chiral imine formed from a trisubstituted cyclic α,β‐unsaturated aldehyde with >98 % ee, giving rise to the stereoselectively substituted building block possessing the A–B steroid rings. Further steps included the construction of the side chain containing the triple bond, and the obtained enyne was subjected to a Pauson–Khand reaction that furnished stereoselectively an intermediate tetracyclic ketone. Further functional group transformations yielded the target compound.

Synthesis of 3-Aryl-3-pyrrolines and 3-Arylpyrroles via Spontaneous Rearrangement of N-Sulfinyl 2-Aryl-2-vinylaziridines

Addition of vinylmagnesium bromide across chiral achloro N-tert-butanesulfinyl ketimines afforded 3-aryl-1-(tert-butanesulfinyl)-3-pyrrolines in high yield (65–91%) after purification by means of recrystallization from diethyl ether. The synthesis of these 3-aryl-3-pyrrolines is explained by initial formation of 2-aryl-2-vinylaziridines which spontaneously rearrange via carbon–nitrogen bond cleavage to form stabilized 1,3-dipolar intermediates which in turn ring closed to 3-pyrrolines.

Synthesis and peptide coupling of protected 2-pyrrolylalanine

2-Pyrrolylalanine has been synthesized in two protected forms and applied in the solution-phase synthesis of a dipeptide. (2 S)- N-(Boc)- N′-(phenylsulfonyl)- and (2 S)- N, N′-bis-(phenylsulfonyl)-3-(2-pyrrolyl)alanines ( 7 and 9) were obtained, respectively, in 14% and 13% overall yields and six and seven steps from oxazolidine β-methyl ester 1, which was derived from l-aspartic acid. Homoallylic ketone 2 was obtained from a copper-catalyzed cascade addition of vinylmagnesium bromide to 1 and converted into pyrrolylalanines 7 and 9 by a sequence featuring subsequent olefin oxidation and Paal-Knorr condensation. Protected pyrrolylalanine 9 was then introduced into a dipeptide.

ChemInform Abstract: The Synthesis of 7-Alkoxyindoles.

Abstract A number of protected 7-hydroxyindoles was prepared by reaction of the protected 2-nitrophenols with vinylmagnesium bromide. Benzhydryl was shown to be the protecting group of choice, giving good yields of the indole and being readily removed for subsequent transformations of the 7-hydroxy function.

ChemInform Abstract: Silicon-Directed Diene Synthesis.

A synthesis of 2-substituted-1,3-dienes is reported which uses silicon as a control element: Eight aldehydes were converted into α-silyl ketones by treatment with trimethylsilylmethylmagnesium chloride and rapid Collins oxidation. Addition of vinylmagnesium bromide to the resulting α-silyl ketones, followed by Peterson elimination, gave a series of dienes. The route was used to make (4S)-3-methylene-t-[(phenylmethoxy)methoxy]pent-1-ene from (–)-ethyl lactate; low asymmetric induction was observed in the Diels–Alder reactions of this diene with diethyl fumarate and N-phenylmaleimide.

ChemInform Abstract: Synthesis of 3′-Ethynylthymidine, 3′-Vinylthymidine, and 3′- Bromovinylthymidine as Potential Antiviral Agents.

Abstract The synthesis of three novel 3′-unsaturated carbon analogues of AZT and FLT is described. The key step in the synthesis is a Cu(I)- catalyzed addition of vinylmagnesium bromide to a 2,3-unsaturated lactone, followed by, in the case of compounds 2 and 3 , elimination reactions of a dibromo-compound.

Asymmetric Synthesis of Functionalized, Monocyclic Chlorocyclobutenes

The selective synthesis of a variety of stereopure monocyclic chlorocyclobutenes is described. These derivatives could be coupled with Grignard reagents; two dienes from coupling with vinylmagnesium bromide reacted smoothly with maleic anhydride to yield illudol-related [4 + 2] cycloadducts.

Tunable Diastereoselection of Biased Rigid Systems by Lewis Acid Induced Conformational Effects: A Rationalization of the Vinylation of Cyclic Nitrones En Route to Polyhydroxylated Pyrrolidines

The diastereofacial selection in addition reactions to biased rigid systems can be modulated by the action of Lewis acids. As an example, the stereoselectivity of the nucleophilic addition of vinyl magnesium bromide (VMB) to cyclic nitrones in the presence of diethylaluminum chloride (DEAC) shows a strong dependence on the temperature and the carbon substituent adjacent at the reaction center; it is remarkable that whereas a high selectivity is obtained at higher temperatures, in the presence of DEAC, a trend to invert the stereochemical course of the reaction is observed at lower temperatures, provided the substituent at C3 of the pyrrolidine ring allows delivery of the vinyl moiety. This behavior and difference in selectivity is to be attributed to the high conformational barriers of the intermediate nitrone-DEAC-VMB complex. A clear inversion of the selectivity is observed at -78 degrees C for the reaction of the nitrone protected as an O-methyl derivative. The present study provides a rationalization for the stereocontrolled addition of nucleophiles to rigid systems (cyclic nitrones).

A Novel, Air-Stable Phosphine Ligand for the Palladium-Catalyzed Suzuki−Miyaura Cross-Coupling Reaction of Chloro Arenes

A novel, air-stable phosphine ligand, prepared from readily available 2-bromonitrobenzene and vinylmagnesium bromide, combines with Pd(CH(3)CN)(2)Cl(2) to afford an effective catalyst for Suzuki-Miyaura cross-coupling of aryl, heteroaryl, and allyl chlorides with phenylboronic acid.

An Expeditious Method for the First Asymmetric Synthesis of Dexoxadrol from the Chiral Pool

A new, straightforward and high-yielding methodology for the asymmetric synthesis of 2-(1,3-dioxolan-4-yl)piperidines is described. This approach involves a highly stereoselective addition of vinylmagnesium bromide to N-(3-butenyl)imines derived from d-glyceraldehyde diphenyl ketal and a ring-closing metathesis reaction as key steps. This procedure was used for the first asymmetric synthesis of (S)-2-[(S)-2,2-diphenyl-1,3-dioxolan-4-yl]piperidine (dexoxadrol) starting from conveniently protected d-mannitol in six steps in 43% overall yield.

ChemInform Abstract: Novel Pyrrolo[2,3-d]pyrimidine Ring Forming Methodology.

Abstract A short, succinct route to biologically active and medicinally important pyrrolo[2,3-d]pyrimidines has been developed starting from readily available acyclic aldehydes. A very efficienttwo step sequence involving a Knoevenagel condensation followed by copper mediated 1,4-conjugate of vinyl magnesium bromide sets up the acyclic precursor. Then, guanidine cyclization followed by a palliduim catalyzed amination reaction or ozonolytic cleavage of the vinyl substituent followed by guanidine cyclization and intramolecular imine formation complete the synthesis.

An efficient total synthesis of the anticancer agent (+)-spisulosine (ES-285) from Garner’s aldehyde

Abstract An efficient total synthesis of (+)-spisulosine (ES-285) was completed in nine steps from (S)-Garner’s aldehyde. The vicinal amino alcohol moiety with anti-configuration was achieved by a highly diastereoselective addition of vinyl magnesium bromide to Garner’s aldehyde. The long hydrocarbon chain of the antitumor natural product was installed via olefin cross metathesis of the benzyl-protected allylic alcohol with an appropriate olefin counterpart followed by hydrogenation.

Synthesis and Properties of a Photoactivatable Analogue of Psychosine (β‐Galactosylsphingosine)

Synthesis and Properties of a Photoactivatable Analogue of Psychosine (β‐Galactosylsphingosine)