SN2 Cyclization Research Articles

Organocatalytic Enantioselective Synthesis of Nitrocyclopropanes Bearing a Thioester Group and Three Stereogenic Centers

AbstractA two‐stage protocol was developed for accessing nitrocyclopropanes that bear a thioester group and three stereogenic centers. This protocol achieves practical overall yields ranging from 54% to 75%, along with high levels of stereoselectivity (single diastereomer with up to 98% ee). Brominated monothiomalonate (Br‐MTM) is used as an α‐bromo thioacetate equivalent, which reacts efficiently with nitroolefins in the presence of a low catalyst loading (0.5 mol%) of cinchona alkaloid squaramide under both “on water” and organic homogeneous conditions. The obtained α‐bromo‐γ‐nitrothioesters undergo an anti‐selective decarboxylation and intramolecular SN2 cyclization process, leading to the formation of desired cyclopropanes. Control experiments were conducted alongside computational studies in order to gain insights into the observed stereoselectivities.

Amino-cyclopropenium H-bonding organocatalysis in cycloaddition of glycidol and isocyanate to oxazolidinone

We developed a kind of neutral organocatalyst amino-cyclopropenium halide to facilitate the [3 + 2] cycloaddition of glycidol and isocyanate to prepare optical active oxazolidinone. Glycidol coupling with isocyanate followed by 5-exo-tet-type cyclization in the presence of organic ion pair. The mild H-bonding coordination between catalyst and substrate prevented the non-selective ring-opening of glycidols and racemization of products. Rather, the cation and anion species activated the epoxy sites and enhanced the nucleophile ability of amide sites, respectively. NMR titrations and control experiments demonstrated the crucial role of H-bonding in cycloaddition reactions. X-ray diffraction (XRD) verified the configuration of intermediate and product, indicating an SN2 cyclization occurred in the process. HPLC analysis of the chiral oxazolidinones unveiled a high enantiomeric excess, signifying the ion pair has excellent stereochemical control. This work provided a simple, efficient, and large-scalable approach to synthesizing 4-hydroxymethyl oxazolidinones.

Asymmetric Total Synthesis of Senepodine F.

The first asymmetric total synthesis of the Lycopodium alkaloid senepodine F, which contains a decahydroquinoline ring (AB-ring) and a quinolizidine ring (CD-ring) connected by a methylene tether, has been achieved. The key steps of this synthesis include an organocatalytic asymmetric Diels-Alder reaction, a diastereoselective intramolecular aza-Michael reaction, and an intramolecular SN2 cyclization to construct multisubstituted nitrogen-containing heterocycles. In addition, our total synthesis led to the stereochemical reassignment on the decahydroquinoline ring of senepodine F.

Asymmetric Total Synthesis and Structure Elucidation of Huperzine H.

A first asymmetric total synthesis of huperzine H has been achieved in a 12% overall yield from commercially available (+)-pulegone. The key steps of this synthesis include a highly diastereoselective Mukaiyama-Michael addition reaction of a pyrrole bearing a silyl enol ether and an intramolecular SN2 cyclization reaction with iodinated pyrrole acting as an effective nucleophile for the formation of the nine-membered ring. As a result, the relative and absolute stereochemistry of huperzine H is established.

Three-Component Condensation of Pyridinium Ylides, β-Ketonitriles, and Aldehydes with Divergent Regioselectivity: Synthesis of 4,5-Dihydrofuran-3- and 2H-Pyran-5-carbonitriles.

A library of trans-4,5-dihydrofuran-3-carbonitriles was synthesized in a diastereoselective manner in good yields by the three-component reaction of β-ketonitriles, carbonyl- and semistabilized pyridinium ylide precursors, and aldehydes in the presence of piperidine. This one-pot transformation generates two C-C and one C-O bond and proceeds through a cascade Knoevenagel condensation, a Michael addition, and intramolecular SN2 cyclization. Formation of cyclopropanecarbonitrile derivatives, which in some cases were obtained as major products, was found to be a competing reaction. The use of arylglyoxals changes regioselectivity and leads to 2-hydroxy-2H-pyran-5-carbonitriles.

Total Synthesis of (−)‐Lepadin F based on a Stereoselective Diels–Alder Reaction Controlled by a Ketolactone‐type Dienophile

An efficient approach to the type III lepadin alkaloids (lepadins F and G) has been developed through a key Diels-Alder reaction, in which a novel ketolactone-type dienophile with chiral diol unit is employed to generate the desirable all-cis-trisubstituted cyclohexene with excellent regio- and stereoselectivity control. The subsequent selective sulfonylation of the diol unit followed by SN 2 cyclization under hydrogenation conditions could construct the substituted piperidine ring. By using this approach, (-)-lepadin F is synthesized from ethyl l-lactate for the first time.

A Short and Efficient Enantioselective Synthesis of (+)‐(2S,3S,5S)‐epi‐Muscarine

AbstractA short, efficient and novel enantioselective general approach for the synthesis of muscarine alkaloid and its application to the asymmetric synthesis of epi‐muscarine from readily available (R)‐PMB glycidyl ether as starting material is described. Key transformations include Sharpless asymmetric dihydroxylation (AD), regioselective epoxide ring opening and intramolecular SN2 cyclization.

Regioselective Synthesis of Functionalized Dihydropyrones via the Petasis Reaction.

A novel synthesis methodology for the construction of functionalized dihydropyrones has been developed with amines, glyoxylic acid, and 4-substituted-1,2-oxaborol-2(5H)-ols from the Petasis reaction. Mechanistic investigation indicated the intermolecular SN2 cyclization to provide 3,6-dihydro-2H-pyran-2-ones (3,6-DHP) and 5,6-dihydro-2H-pyran-2-ones (5,6-DHP) in one step with moderate to excellent yields.

Asymmetric Synthesis of 2'-C-Methyl-4'-selenonucleosides as Anti-Hepatitis C Virus Agents.

In search of a new template for anti-hepatitis C virus (HCV) agents, we designed and synthesized the 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides and their phosphoramidate prodrugs to replace a furanose oxygen of anti-HCV nucleos(t)ides with a selenium atom on the basis that selenium is a chemical isostere of oxygen. These nucleosides are expected to show different physicochemical properties such as better lipophilicity which might enhance the penetration across cell membranes and the conformational constraint induced by a bulky selenium atom in the sugar ring. The 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides 8 and 9 were synthesized from 2-C-methyl-d-ribono-γ-lactone (14) via construction of 2-C-methyl-d-selenosugar 18 through C-4 epimerization and SN2 cyclization with Se2- as key steps. The key 4'-selenosugar was converted to the 2'-C-methyl-4'-selenopyrimidine and -purine nucleosides using Pummerer-type rearrangement and Vorbrüggen glycosylation, respectively. In addition, the ProTide strategy has been applied to synthesize the adenine and uracil phosphoramidate derivatives 10a and 10b to overcome the limitations associated with parent nucleosides such as inefficient conversion to their corresponding 5'-monophosphate form and poor cellular uptake. The regio- and stereochemistry of 4'-selenonucleosides were confirmed by 2D NOESY NMR spectroscopy and X-ray crystallography. None of the final pyrimidine and purine nucleosides and their prodrugs exhibited significant anti-HCV activity up to 100 μM.

Synthesis of the C6–C18 bis-tetrahydrofuran fragment of the proposed structure of iriomoteolide-2a via stepwise double SN2 cyclization reactions

The C6–C18 bis-tetrahydrofuran (bis-THF) fragment of the proposed structure of iriomoteolide-2a has been synthesized via stepwise double intramolecular SN2-type etherifications. The C11 and C16 stereogenic centers could be secured in the forms of propargyl alcohols by asymmetric transfer hydrogenation of the corresponding propargyl ketones. The C9–C12 THF ring was first constructed via a tandem asymmetric dihydroxylation (AD)–SN2 sequence while the C13–C16 THF ring was later installed via an intramolecular SN2 reaction of a chiral propargyl mesylate. During the latter THF ring formation, epimerization at the propargylic carbon was not observed. Since the initially proposed (9R,11S,12R) configuration of iriomoteolide-2a has recently been revised to (9S,11R,12S), the established synthesis of the C6–C18 bis-THF fragment could be easily amended by using the opposite enantiomers of the chiral ligands for AD and asymmetric transfer hydrogenation.

Biomimetic Syntheses of (±)‐Isopalhinine A, (±)‐Palhinine A, and (±)‐Palhinine D

AbstractThe first total synthesis of isopalhinine A, as well as unified syntheses of palhinine A and palhinine D, were successfully accomplished by means of a biomimetic strategy that proceeds through a bioinspired 5/6/6/9 tetracyclic intermediate, which mimics the amino ketone form of palhinine D. An early‐stage direct SN2 cyclization to construct the nine‐membered azonane ring minimized the transannular strain that would otherwise be increased by the twisted nature of the isotwistane skeleton. Then, a diastereoselective Diels–Alder reaction of a masked ortho‐benzoquinone using the nine‐membered ring as a steric shielding group furnished a functionalized 6/6/9 tricyclic skeleton and established the desired stereochemistry at the C3, C7, C12, and C15 positions in one step. A thiol‐mediated acyl radical cyclization gave the bioinspired intermediate bearing three differentiated oxygen‐containing functional groups, from which all three total syntheses could be completed in either two or three additional steps.

A General Diastereoselective Strategy for Both cis- and trans-2,6-Disubstituted Tetrahydropyrans: Formal Total Synthesis of (+)-Muconin.

A protocol for general diastereoselective tandem dihydroxylation followed by SN2 cyclization was developed for the convenient and efficient synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans from ζ-mesyloxy α,β-unsaturated esters. The application of this novel method was demonstrated through the concise formal synthesis of (+)-muconin, a nonclassical acetogenin, with sequential THP-THF ring formation.

Bicyclic Heterocycles from Levulinic Acid through a Fast and Operationally Simple Diversity‐Oriented Multicomponent Approach

Levulinic acid, which is one of the most important renewable building blocks derived from lignocellulosic biomass, has been converted in a diversity‐oriented manner into two families of drug‐like bicyclic nitrogen heterocycles. The methodology, endowed with high step economy and operational simplicity, is based on an Ugi multicomponent reaction, which employs amino alcohols as components, followed by a SN2 cyclization. Noteworthy is the successful synthesis of hexahydro pyrrolodiazepinediones, since the cyclization of the isocyanide‐derived secondary amide onto an alcohol to give a seven‐membered ring was unprecedented. Also enantiopure products have been prepared by using chiral amino alcohols.

A radical S-adenosyl-L-methionine enzyme and a methyltransferase catalyze cyclopropane formation in natural product biosynthesis

Cyclopropanation of unactivated olefinic bonds via addition of a reactive one-carbon species is well developed in synthetic chemistry, whereas natural cyclopropane biosynthesis employing this strategy is very limited. Here, we identify a two-component cyclopropanase system, composed of a HemN-like radical S-adenosyl-l-methionine (SAM) enzyme C10P and a methyltransferase C10Q, catalyzes chemically challenging cyclopropanation in the antitumor antibiotic CC-1065 biosynthesis. C10P uses its [4Fe-4S] cluster for reductive cleavage of the first SAM to yield a highly reactive 5′-deoxyadenosyl radical, which abstracts a hydrogen from the second SAM to produce a SAM methylene radical that adds to an sp2-hybridized carbon of substrate to form a SAM-substrate adduct. C10Q converts this adduct to CC-1065 via an intramolecular SN2 cyclization mechanism with elimination of S-adenosylhomocysteine. This cyclopropanation strategy not only expands the enzymatic reactions catalyzed by the radical SAM enzymes and methyltransferases, but also sheds light on previously unnoticed aspects of the versatile SAM-based biochemistry.

Synthesis of the C18–C26 tetrahydrofuran-containing fragment of amphidinolide C congeners via tandem asymmetric dihydroxylation and SN2 cyclization

The C18–C26 fragment of amphidinolide C congeners has been synthesized starting from methyl acetoacetate in 14 steps in >17.0% overall yield. The C20 stereogenic center was secured by asymmetric hydrogenation of a β-keto ester and the configuration at both C23 and C24 was introduced by asymmetric dihydroxylation (AD). The trans-2,5-disubstituted tetrahydrofuran ring was assembled via the tandem AD–SN2 sequence. The latter protocol could be employed for accessing the corresponding cis-2,5-disubstituted tetrahydrofuran rings from the same alkene substrates simply by choosing a suitable AD ligand. Moreover, functional group compatibility was observed for the Ru(II)-catalyzed hydrogenation of β-keto esters and the Pd(0)–Cu(I)-catalyzed Sonogashira cross-coupling reaction. These findings should be valuable for general synthetic design and application.

Diversity‐Oriented Synthesis of Various Enantiopure Heterocycles by Coupling Organocatalysis with Multicomponent Reactions

Chiral, enantiopure 1,3‐amino alcohols, obtained through an organocatalytic Mannich reaction, have been used as starting materials for a concise sequence involving a diastereoselective Ugi reaction followed by various types of SN2 cyclization. In this way, different enantiopure heterocycles have been prepared, with both scaffold and decoration diversity (up to four diversity inputs).

Synthesis of Chiral Azabicycles from Pyroglutaminols

The stereocontrolled synthesis of a range of substituted bicyclic morpholine and piperazine derivatives is reported from substituted pyroglutaminols via an intramolecular SN2 cyclization as the key step. This enantiospecific approach toward chiral bicyclic morpholines and piperazines offers new opportunities to access these challenging ring systems, which are becoming increasingly common motifs in drug discovery.

Complementary asymmetric routes to fused tricyclic (R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolines and (R)-1,2,3,4,5,5a,6,7-octahydro-[1,4]diazepino[1,2-a]quinolines

Two distinct enantioselective approaches to (R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolines and (R)-1,2,3,4,5,5a,6,7-octahydro-[1,4]diazepino[1,2-a]quinolines, low MW tricyclic organic scaffolds with a high degree of molecular complexity, are described. The key transformation in route 1 is the lateral lithiation of an N-Boc-o-toluidine and dianion trap with (S)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane. An intramolecular SN2 cyclization then forms the optically pure tetrahydroquinoline core. Route 2 involves the coupling of (R)-2-(4-benzyl-1-(Boc)piperazin-2-yl)acetaldehyde or (R)-2-(4-benzyl-1-(Boc)-1,4-diazepan-2-yl)acetaldehyde with an aryllithium and a subsequent intramolecular SNAr reaction to form the tricycle. Both synthetic routes were valuable for preparing and identifying ligands targeting GPCRs expressed in the central nervous system (CNS).

Niizalactams A-C, Multicyclic Macrolactams Isolated from Combined Culture of Streptomyces with Mycolic Acid-Containing Bacterium.

A terrestrial bacterium, Streptomyces sp. NZ-6, produced niizalactams A-C (1-3), unprecedented di- and tricyclic macrolactams, by coculturing with the mycolic acid-containing bacterium Tsukamurella pulmonis TP-B0596. Their complete structures, including absolute configurations, were elucidated on the basis of spectroscopic data and chemical derivatization. Their unique skeletons are proposed to be biosynthesized from a common 26-membered macrolactam intermediate by SN2 cyclization or an intramolecular Diels-Alder reaction.

Total Synthesis of (+)‐Petromyroxol, a Marine Natural Product

AbstractAn efficient total synthesis of (+)‐petromyroxol, a marine natural product, is described. The synthesis utilizes the Sharpless asymmetric dihydroxylation (AD), intramolecular SN2 cyclization and stereoselective Grignard reaction as key steps.