Diastereoselective Addition Research Articles

Synthesis of Pyrrolidine-2-ylidenes from Isoxazolines and Allenes.

A diastereoselective addition and rearrangement reaction has been developed for the synthesis of pyrrolidine-2-ylidenes from NH-isoxazolines and electron-deficient allenes. This method proceeds via the rearrangement of a proposed N-alkenylisoxazoline intermediate to generate densely functionalized pyrrolidine-2-ylidenes under simple catalyst-free conditions that tolerate ketone substituents and install relative stereochemistry at positions 3 and 4 of the heterocycle. Reaction optimization and the substrate scope are described in addition to studies evaluating the reactivity of the gem-dione and enaminone groups of the products.

Photoinduced Stereoselective Giese Addition on Coumarins

AbstractDiastereoselective Giese addition on coumarin-3-carboxylate bearing a chiral auxiliary with N-hydroxyphthalimide ester to generate the corresponding alkylated adduct has been explored. Among screened chiral auxiliaries, bulkier one with appropriate steric hindrance is better for diastereoselective addition. Mechanistic studies involving fluorescence studies and On/Off experiments shed insight onto the plausible reaction pathway.

Practical Synthesis of Macrobicyclic Thiolincosamines.

Scalable syntheses of the northern macrobicyclic thiolincosamine fragments of two structurally complex antibiotic candidates, BT-33 and cresomycin, are presented. A key transformation in each route is the highly diastereoselective addition of a putative allenylzinc nucleophile to a common Ellman sulfinimine intermediate using a zinc-promoted Barbier-type propargylation protocol that is detailed herein. These transformations proceed with dynamic kinetic resolution and use just 1.2 equiv of each respective propargyl bromide precursor.

Diastereoselective Addition of Lithiated Allenyl Sulfones to Nonracemic Sulfinimines: Asymmetric Synthesis of Diverse Heterocycles.

The addition of lithiated allenyl sulfones to nonracemic sulfinimines furnished sulfinamides possessing the allenyl sulfonyl moiety with excellent diastereoselectivity. The formed products are transformed into different heterocycles, including the synthesis of pyrroline, pyran, and functionalized benzopyran.

Functionalized α‐Fluorinated Amines from Imines and Enol Ethers

AbstractWe report the addition reaction of lithium enol ethers to fluoroalkyl imines. A range of different fluoroalkyls and lithiated reagents are well tolerated. Diastereoselective addition of lithium vinyl ethers to fluoroalkyl N‐tert‐butylsulfinylimines is disclosed, providing enantiomerically enriched α‐fluorinated amines in up to 98% yield. This general approach led to the diastereoselective formation of various amino alcohols and amino ethers, which are difficult to obtain by other methods.

Rh(II)-Catalyzed Enantioselective S-Alkylation of Sulfenamides with Acceptor-Acceptor Diazo Compounds Enables the Synthesis of Sulfoximines Displaying Diverse Functionality.

The Rh(II)-catalyzed enantioselective S-alkylation of sulfenamides with α-amide diazoacetates at 1 mol % catalyst loading to obtain sulfilimines in high yields and enantiomeric ratios of up to 99:1 is reported. The enantioenriched sulfilimine products incorporate versatile amide functionality poised for further elaboration to diverse sulfoximines with multiple stereogenic centers, including by highly diastereoselective sulfilimine and sulfoximine α-alkylation with alkylating agents and epoxides and by interconversion of the amide to N-tert-butanesulfinyl aldimines, followed by diastereoselective additions.

A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease.

Isofagomine (IFG) and its analogues possess promising glycosidase inhibitory activities. However, a flexible synthetic strategy toward both C5a-functionalized IFGs remains to be explored. Here we show a practical synthesis of C5a-S and R aminomethyl IFG-based derivatives via the diastereoselective addition of cyanide to cyclic nitrone 1. Nitrone 1 was conveniently prepared on a gram scale and in high yield from inexpensive (-)-diethyl D-tartrate via a straightforward method, with a stereoselective Michael addition of a nitroolefin and a Nef reaction as key steps. A 268-membered library (134 × 2) of the C5a-functionalized derivatives was submitted to enzyme- or cell-based bio-evaluations, which resulted in the identification of a promising β-glucocerebrosidase (GCase) stabilizer demonstrating a 2.7-fold enhancement at 25 nM in p.Asn370Ser GCase activity and a 13-fold increase at 1 μM in recombinant human GCase activity in Gaucher cell lines.

Total Synthesis of Pallamolides A-E.

We have achieved the first total synthesis of pallamolides A-E. Of these compounds, pallamolides B-E possess intriguing tetracyclic skeletons with novel intramolecular transesterifications. Key transformations include highly diastereoselective sequential Michael addition reactions to construct the bicyclo[2.2.2]octane core with the simultaneous generation of two quaternary carbon centers, a one-pot SmI2-mediated intramolecular ketyl-enoate cyclization/ketone reduction to generate the key oxabicyclo[3.3.1]nonane moiety, and an acid-mediated deprotection/oxa-Michael addition/β-hydroxy elimination cascade sequence to assemble the tetracyclic pallamolide skeleton. Kinetic resolution of ketone 14 through Corey-Bakshi-Shibata reduction enabled the asymmetric synthesis of pallamolides A-E.

Total Synthesis of Pallamolides A‐E

We have achieved the first total synthesis of pallamolides A‐E, of which pallamolides B‐E possess intriguing tetracyclic skeletons with novel intramolecular transesterifications. Key transformations include highly diastereoselective sequential Michael additions to construct the bicyclo[2.2.2]octane core with simultaneous generation of two quaternary carbon centers, a one‐pot SmI2‐mediated intramolecular ketyl‐enoate cyclization/ketone reduction to generate the key oxabicyclo[3.3.1]nonane moiety, and an acid‐mediated deprotection/oxa‐Michael addition/β‐hydroxy elimination cascade sequence to assemble pallamolides tetracyclic skeletons. Kinetic resolution of ketone 14 via Corey‐Bakshi‐Shibata reduction enabled the asymmetric synthesis of pallamolides A‐E.

Effective and Scalable General Method for the Preparation of Enantiomeric (α‐Aminoalkyl)dimethylphosphine Oxides

AbstractThe Ti(OPr‐i)4‐mediated three–component condensation of enantiomeric Ellman's amides, dimethylphosphine oxide, and aliphatic, aromatic or heteroaromatic aldehydes proceeds in high yields and diastereoselectivities enabling the rapid, scalable and general asymmetric synthesis of (α‐amino)dimethylphosphine oxide derived compounds bearing alkyl, cycloalkyl or hetaryl group at the chiral carbon atom. Asymmetric synthesis of α‐amino‐α‐polyfluoroalkyl dimethylphosphine oxides was accomplished through diastereoselective addition of dimethylphosphine oxide to enantiomeric Ellman's aldimines, RFCH=NS(O)tert‐Bu (RF=CF3, CHF2, PhCF2).

Elektrophile Aktivierung von S−Si‐Reagenzien mit Silyliumionen für deren regio‐ und diastereoselektive Addition an C−C‐Mehrfachbindungen

AbstractEs wird eine regioselektive silyliumionvermittelte Thiosilylierung von internen C−C‐Dreifachbindungen mit Kontrolle der Doppelbindungsgeometrie beschrieben. Im Zuge dieser Zweikomponentenreaktion eines Alkins und eines Thiosilans werden sowohl eine C(sp2)−S‐ als auch eine C(sp2)−Si‐Bindung mit einer trans‐Beziehung gebildet. Die hierdurch entstandene orthogonal funktionalisierte C−C‐Doppelbindung lässt sich chemoselektiv defunktionalisieren oder unter Erhalt der Alkenkonfiguration in Kreuzkupplungsreaktionen weiter umsetzen. Die Reaktionsvorschrift ist ebenfalls auf die regio‐ und diastereoselektive Thiosilylierung von terminalen Allenen anwendbar, was zu allylischen Thioethern, die eine Vinylsilaneinheit enthalten, führt. Diese Reaktionen beinhalten die elektrophile Aktivierung des S−Si‐Reagenzes, ein silyliertes Thiophenol und sogar Alkylthiolderivat, durch eine in situ erzeugte Carbokationzwischenstufe. Der Katalysecyclus wird durch ein bissilyliertes Aryl‐ oder Alkylsulfoniumion als ein Shuttle für das kationische Siliciumelektrophil aufrechterhalten. Dessen unabhängige Darstellung und strukturelle Charakterisierung durch Röntgenbeugung werden ebenfalls berichtet.

Electrophilic Activation of S-Si Reagents by Silylium Ions for Their Regio- and Diastereoselective Addition Across C-C Multiple Bonds.

A regioselective silylium-ion-promoted thiosilylation of internal C-C triple bonds with control over the double bond geometry is described. Both a C(sp2)-S and a C(sp2)-Si bond are formed with a trans relationship in this two-component reaction of an alkyne and a thiosilane. The resulting orthogonally functionalized C-C double bond can be chemoselectively defunctionalized or further processed by cross-coupling reactions with the alkene configuration retained. The procedure is also applicable to the regio- and diastereoselective thiosilylation of terminal allenes to arrive at allylic thioethers containing a vinylsilane unit. These reactions involve the electrophilic activation of the S-Si reagent, both a silylated thiophenol and even alkylthiol derivative, by an in situ-generated carbocation intermediate. The catalytic cycle is maintained by a bissilylated aryl- or alkylsulfonium ion as a shuttle for the cationic silicon electrophile. Its independent preparation and structural characterization by X-ray diffraction are also reported.

Die Totalsynthese von Isoxeniolid A**

AbstractIsoxeniolid A ist ein hochgespanntes marines Diterpenoid aus der Familie der Xenicane. Es steht repräsentativ für eine Unterfamilie von Xenicanen, deren 9‐gliedriger Ring eine allylische Hydroxygruppe aufweist; derartige Xenicane wurden bisher nicht als Zielmoleküle von Totalsynthesen verfolgt. Wir beschreiben hier die erste asymmetrische Totalsynthese eines derartigen Xenicans, nämlich des Isoxeniolid A. Dabei lag der Schlüssel zum Aufbau des besonders herausfordernden E‐konfigurierten Cyclononenrings in einer diastereoselektiven intramolekularen Nozaki–Hiyama—Kishi‐Reaktion. Andere wichtige Transformationen waren eine enzymatische Desymmetrisierung zur Kontrolle der absoluten Stereochemie, eine diastereoselektive Cuprat‐Addition und die Verwendung eines bifunktionalen Vinylsilan‐Bausteins. Unsere Synthesestrategie ermöglicht auch den Zugang zur enantiomeren Form des Naturstoffs sowie prinzipiell zu einer Vielzahl anderer natürlicher Xenicane und synthetischer Analoga für Struktur‐Aktivitäts‐Untersuchungen.

Total Synthesis of Isoxeniolide A.

Isoxeniolide A is a highly strained xenicane diterpenoid of marine origin. This natural product is representative for a subfamily of xenicanes incorporating an allylic hydroxy group in the nine-membered ring; members of this xenicane subfamily so far have not been targeted by total synthesis. Herein, we describe the first asymmetric total synthesis of isoxeniolide A. Key to forming the challenging E-configured cyclononene ring was a diastereoselective intramolecular Nozaki-Hiyama-Kishi reaction. Other important transformations include an enzymatic desymmetrization for absolute stereocontrol, a diastereoselective cuprate addition and the use of a bifunctional vinyl silane building block. Our strategy also permits access to the enantiomer of the natural product and holds potential to access a multitude of xenicane natural products and analogs for structure-activity relationship studies.

Stereocontrolled synthesis of the aconitine D ring from D-glucose.

The synthesis of a fully oxygenated aconitine D ring precursor from (D)-(+)-glucose is described. The route features a highly diastereoselective alkynyl Grignard ketone addition and a base-mediated enelactone to 1,3-diketone rearrangement.

Enantio- and diastereoselective conjugate addition of pyridyl alkyl ketones to enones by Cu(ii)-Lewis acid/Brønsted base catalysis

Cu(ii) Lewis acid/Brønsted base catalysis was employed to achieve enantio- and diastereoselective conjugate additions of pyridyl alkyl ketones to enones, resulting in the formation of various 1,5-diketones with vicinal stereocenters.

Regio‐ and Diastereoselective Conjugate Addition of Grignard Reagents to Chiral Fluoroalkyl α,β‐Unsaturated N‐tert‐Butanesulfinyl Ketimines: Synthesis of Optically Active Fluorinated Enamines and Derivatives

AbstractA regio‐ and diastereoselective conjugate addition reaction of Grignard reagents to fluoroalkyl α,β‐unsaturated N‐tert‐butanesulfinyl ketimines was disclosed. A range of different fluoroalkyls and Grignard reagents were well tolerated, giving up to 99% diastereomeric and regioisomeric ratios. This reaction provided a straightforward method for the synthesis of a variety of enantiomerically enriched α‐fluorinated enamines and derivatives which are difficult to achieve with other methods.

Diastereoselective Synthesis of Phosphinic Dipeptide Isosteres: Domino Chirality Transfer during a Stereocontrolled P-Michael Reaction.

A highly diastereoselective P-Michael addition of chiral aminophosphinic acids to achiral acrylates has been developed, leading to phosphinic dipeptide isosteres in high yields and dr of up to >50:1. The method allows for the diastereoselective preparation of target compounds without the need for chiral auxiliaries or P-chiral substrates. A possible mechanistic explanation involves a domino chirality transfer from the aminophosphinic acid to the P center, amplified by a crucial benzhydryl ester group, and then to the α-carbon.

Enantiomeric N‐(tert‐Butylsulfinyl) Polyfluoroalkyl Aldimines in aza‐Henry Reaction: Effective Route to Chiral Polyfluoroalkyl Nitroamines and Diamines

AbstractA highly diastereoselective addition of nitromethane to the C=N bond of enantiomeric fluorine containing Ellman's aldimines, RFCH=NS(O)tert‐Bu (RF=CF3, CF2Br, C2F5, HC2F4), has been successfully developed. The synthetic potential of the resulting β‐nitrosulfinylamides was demonstrated through their conversion into optically active α‐fluoroalkylated 1,3‐nitroamines, 1,3‐diamines, and 4‐fluoroalkylated imidazolidin‐2‐ones.

Applications of chiral sulfinyl auxiliaries in the asymmetric synthesis of fluorinated amines and amino acids

This review article covers the developments made in collaboration by groups of Professors V. P. Kukhar and P. Bravo to the synthetic applications of sulfinyl compounds as versatile chiral auxiliaries for asymmetric preparation of fluorinated amines and amino acids. The potential of the sulfinyl chiral auxiliaries in the field of stereoselective transformations of fluorinated substrates is demonstrated by diastereoselective methylene transfer from diazomethane to the carbonyl of β-keto-γ-fluoroalkyl sulfoxides as a general approach for preparation of various fluorinated oxirane derivatives, diastereoselective sulfoxide anions addition to fluorinated imines leading to convenient preparation of α-fluoroalkyl α-amino acids, hydroxy amines, and amines, diastereoselective Mannich-type reaction between N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine and protected alkyl glycolates furnishing β-trifluoromethyl isoserine derivatives and diastereoselective additions of phosphite or α-phosphonate anions to N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine using for synthesis of trifluoromethylated α- and β-aminophosphonic acids. Furthermore, diastereoselective additions of Reformatsky reagent derived from bromodifluoroethyl acetate as well as α,α-difluorophosphonate anions to N-p-toluenesulfinyl imines allowing convenient preparation of a,a-difluoro-b-amino acids and α,α-difluoro-β-amino phosphonates in enantiomerically pure form are described. Effect of fluorine on the mechanism and stereochemical outcome of these reactions is briefly discussed