Highly stereoselective Michael reduction/intramolecular Michael reaction cascade to synthesize trans-stereodiad comprising an all-carbon quaternary stereogenic center

A highly stereoselective Michael reduction/intramolecular Michael reaction cascade is described. The cascade is initiated by the regioselective Michael reduction of an α-methylidene ester with L-Selectride. This is followed by the highly stereoselective intramolecular Michael reaction which efficiently constructs a six-membered carbocyclic ring with formation of the trans-stereodiad, composed of an all-carbon quaternary center and a tertiary stereogenic center. The stereoselectivity is perfectly controlled by the choice of alkene geometry in the Michael acceptor.     

A stereoselective cyclisation cascade mediated by SmI2–H2O: synthetic studies towards stolonidiol

A cascade reaction involving sequential conjugate reduction, stereoselective aldol cyclisation and chemoselective lactone reduction mediated by SmI₂–H₂O provides access to a cyclopentanol bearing two vicinal quaternary stereocentres with good stereocontrol. The functionalised cyclopentanol product has been converted to a key intermediate in ongoing asymmetric studies towards stolonidiol.     

New reactions of alkynes with ketones in superbasic media

The present work reviews new reactions of alkynes with ketones in the superbasic media MOH—DMSO (M = Na, K, Cs) and KOBu^t—DMSO: the stereoselective nucleophilic addition of deprotonated ketones to the triple bond to form the E-isomers of β,γ-enones; vinylation of tertiary acetylenic alcohols that formed in situ from acetylene and ketones; the direct synthesis of vinyl ethers of tertiary acetylenic alcohols from acetylene and ketones; the stereoselective synthesis of dispirocyclic ketals containing the Z-ethylene fragment from arylalkynes and two molecules of a cyclic ketone; the stereoselective cascade synthesis of hexahydroazulenones from two arylalkyne molecules and 2-alkylcyclohexanones; the stereoselective cascade assembly of 7-methylidene-6,8-dioxabicyclo[3.2.1]octanes from two acetylene molecules and two ketone molecules; the stereoselective cascade synthesis of 7-methylidene-6,8-dioxabicyclo[3.2.1]octanes from acetylenes and 1,5-diketones; and the three-component cascade reaction of acetylene, ketones, and oximes to afford 4-methylidene-3-oxa-1-azabicyclo-[3.1.0]hexanes.     

Total synthesis of (−)-nakadomarin A: alkyne ring-closing metathesis

A 13-step, highly stereoselective synthesis of (−)-nakadomarin A has been achieved using the combination of a bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, an alkyne ring-closing metathesis/syn-reduction, and furan/iminium ion cyclization/reduction as key steps.     

A total synthesis of tarchonanthuslactone exploiting N-pyrrole carbinols as efficient stereocontrolling elements

[reaction: see text] A short stereoselective total synthesis of the polyketide natural product, tarchonanthuslactone, has been achieved. The key sequence involves the first reported catalytic enantioselective reduction of an N-acyl pyrrole and subsequent use of this stereocenter in a diastereoselective reductive cascade. This proceeded with unprecedentedly high stereocontrol and offered an elegant method of generating the desired syn stereochemistry present in the final target in one step.     

Four-component stereoselective synthesis of tetracyano-substituted piperidines

Research on Chemical Intermediates - A novel four-component stereoselective synthesis of polysubstituted piperidines is reported. The Knoevenagel–Michael–Mannich cascade of two...     

Whole‐Cell Biocatalysts for Stereoselective C−H Amination Reactions

Enantiomerically pure chiral amines are ubiquitous chemical building blocks in bioactive pharmaceutical products and their synthesis from simple starting materials is of great interest. One of the most attractive strategies is the stereoselective installation of a chiral amine through C?H amination, which is a challenging chemical transformation. Herein we report the application of a multienzyme cascade, generated in a single bacterial whole‐cell system, which is able to catalyze stereoselective benzylic aminations with ee values of 97.5 %. The cascade uses four heterologously expressed recombinant enzymes with cofactors provided by the host cell and isopropyl amine added as the amine donor. The cascade presents the first example of the successful de novo design of a single whole‐cell biocatalyst for formal stereoselective C?H amination.     

Bioinspired Synthesis of (+)‐Cinchonidine Using Cascade Reactions

The development of efficient syntheses of complex natural products has long been a major challenge in synthetic chemistry. Designing cascade reactions and employing bioinspired transformations are an important and reliable means of achieving this goal. Presented here is a combination of these two strategies, which allow efficient asymmetric synthesis of the cinchona alkaloid (+)‐cinchonidine. The key steps of this synthesis are a controllable, visible‐light‐induced photoredox radical cascade reaction to efficiently access the tetracyclic monoterpenoid indole alkaloid core, as well as a practical biomimetic cascade rearrangement for the indole to quinoline transformation. The use of stereoselective chemical transformations in this work makes it an efficient synthesis of (+)‐cinchonidine.     

Enantioselective Total Syntheses of (−)-20-epi-Vincamine and (−)-20-epi-Eburnamonine by Ir-Catalyzed Asymmetric Imine Hydrogenation/Lactamization Cascade

The Eburnamine-Vincamine alkaloids have been studied intensively over the past six decades for their outstandingly potent vasorelaxation activity. Stereocontrolled assembly of the C20/C21 adjacent chiral centers has been a formidable challenge in the synthesis of this family. Herein, we report a concise stereoselective total synthesis of two trans-ring-fused non-natural analogues, (−)-20-epi-Vincamine and (−)-20-epi-Eburnamonine, that features the following key steps: a) a continuous-flow oxidation/lactam alcoholysis cascade producing the symmetrical dihydro-β-carboline diester precursors, and b) a highly stereoselective Ir/f-Binaphane-catalyzed hydrogenation/lactamization cascade leading to the privileged trans-(20R, 21S) lactam ester scaffold with high-level enantio- and diastereocontrol.     

Application of a new tandem isomerization-aldolization reaction of allylic alcohols to the synthesis of three diastereoisomers of (2R)-1,2-O-isopropylidene-4-methylpentane-1,2,3,5-tetraol

The tandem isomerization-aldolization reaction of (2R)-1,2-O-isopropylidene-4-penten-1,2,3-triol 3 and formaldehyde gives a mixture of two aldol products 2a and 2b. The stereoselective reduction of each compound by l-Selectride affords two diastereoisomers of (2R)-1,2-O-Isopropylidene-4-methylpentane-1,2,3,5-tetraol while a third diastereoisomer is obtained by stereoselective reduction with Me(4)NHB(OAc)(3).     

Synthesis of polyhydroxylated bicyclic tetrahydrofurans and tetrahydropyrans via a stereoselective domino cyclization/reduction reaction

A novel reaction cascade involving a Lewis acid-induced migration of an isopropylidene protecting group followed by the formation of a pyranose or furanose ring and subsequent reduction of the hemiacetal is described. Depending on the reaction conditions, as well as, the stereochemistry of the substrate, polyhydroxylated tetrahydrofurans or tetrahydropyrans can be obtained in reasonable yields. The synthons used in this transformation were prepared via a highly stereoselective one-pot tandem reaction, consisting of a 1,4-Michael addition of vinylmagnesium bromide to d-glucose-derived cyclohexenone followed by aldol reaction with 2,3-O-isopropylidene-d-glyceraldehyde.     

Cascade polycyclization: exploration of a convergent route to access various tricyclic and tetracyclic products related to sterols

The expedient synthesis of tricyclic and tetracyclic compounds via a cascade polycyclization methodology is described. Nazarov substrates (II) containing two Michael acceptors and a cyclohexenone ester (I) underwent cycloaddition followed by intramolecular 1,4-addition to furnish, in a highly stereoselective manner, tricyclic and tetracyclic products (III). Such compounds are interesting intermediates for the synthesis of polycyclic natural and unnatural products.     

Total syntheses of drimane-type sesquiterpenoids enabled by a gold-catalyzed tandem reaction

Development of a gold-catalyzed tandem reaction of 1,7-diynes with both internal and external nucleophiles was realized, which constructed five chemical bonds, two rings, and two stereogenic centers in a single step. Based on the novel cascade transformation, we achieved a unified strategy toward the stereoselective total syntheses of C-15 oxygenated drimane-type sesquiterpenoids and their analogues, which provided the natural products kuehneromycin A, antrocin, anhydromarasmone, and marasmene as a proof-of-concept study.     

Selective Cascade Reaction of Bisallenes via Palladium‐Catalyzed Aerobic Oxidative Carbocyclization–Borylation and Aldehyde Trapping

A cascade reaction, consisting of a palladium‐catalyzed regioselective aerobic oxidative carbocyclization–borylation of bisallenes and a final aldehyde trapping, afforded triene alcohols with high diastereoselectivity. The cascade reaction occurs under mild reaction conditions and proceeds via an allylboron intermediate that is trapped by the aldehyde in a stereoselective manner.     

Lewis acid mediated endo-cyclisation of trimethylsilylmethylenecyclopropyl imines--a stereoselective route to indolizidines

Lewis acid mediated endo-cyclisation of trimethylsilylmethylenecyclopropyl imines provides a stereoselective route to indolizidines via a novel cascade sequence.     

A stereocontrolled synthesis of (+)-saxitoxin

A concise stereoselective total synthesis of (+)-saxitoxin is described. A silver(I)-initiated hydroamination cascade constructs the bicyclic guanidinium ion core from a alkynyl bisguanidine. This sequence creates two C-N bonds, one C-O bond, and three rings and forms a single stereoisomer in a single synthetic transformation. This process enabled us to complete the synthesis of (+)-saxitoxin in 14 steps from N-Boc-l-serine methyl ester.     

STUDIES DIRECTED TOWARD THE SYNTHESIS OF NAKADOMARIN A

The application of a Pummerer-initiated tandem reaction cascade leads to the highly stereoselective formation of the tetracyclic core of nakadomarin A.     

Cascade enantioselective synthesis of γ-aryl-γ-butyrolactones with a delayed stereoselective step

Enantioselective synthesis of γ-aryl-γ-butyrolactones is achieved using (S)-1-phenylethylamine as a chiral auxiliary. The synthesis involves cascade formation-destruction-formation of the chiral centre with a delayed stereoselective step. The actual stereoselective step has been found to be intramolecular nucleophilic attack on a diastereotopic carbocation formed, thereby resulting in the formation of non-racemic γ-aryl-γ-butyrolactones.     

Whole‐Cell‐Catalyzed Multiple Regio‐ and Stereoselective Functionalizations in Cascade Reactions Enabled by Directed Evolution

Biocatalytic cascade reactions using isolated stereoselective enzymes or whole cells in one‐pot processes lead to value‐added chiral products in a single workup. The concept has been restricted mainly to starting materials and intermediate products that are accepted by the respective wild‐type enzymes. In the present study, we exploited directed evolution as a means to create E. coli whole cells for regio‐ and stereoselective cascade sequences that are not possible using man‐made catalysts. The approach is illustrated using P450‐BM3 in combination with appropriate alcohol dehydrogenases as catalysts in either two‐, three‐, or four‐step cascade reactions starting from cyclohexane, cyclohexanol, or cyclohexanone, respectively, leading to either (R,R)‐, (S,S)‐, or meso‐cyclohexane‐1,2‐diol. The one‐pot conversion of cyclohexane into (R)‐ or (S)‐2‐hydroxycyclohexanone in the absence of ADH is also described.     

Stereoselective convergent synthesis of a trans-fused polycyclic ether ring system including a 4-hydroxy-5-methyl-tetrahydropyran ring

[reaction: see text] Stereoselective convergent synthesis of a trans-fused 6-6-6-6-membered tetracyclic ether ring system including 4alpha- or 4beta-hydroxy-5-methyl-tetrahydropyran was achieved. The key reactions involve the acetylide-aldehyde coupling of two tetrahydropyrans, intramolecular hetero-Michael cyclization of enone, stereoselective reduction of enone, hydroboration, intramolecular acetalization, and stereoselective reduction of the acetal with Et(3)SiH-TMSOTf.