Protected Hydroxymethyl Group Research Articles

Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy

Heating aldehydes that contain a protected hydroxymethyl group, a tethered alkyl chloride and a tethered alkenyl group at the α-position of the aldehyde with an amine sets up a cascade (tandem) reaction sequence involving condensation to an intermediate imine, then cyclization and formation of an intermediate azomethine ylide and then intramolecular dipolar cycloaddition. The fused tricyclic products are formed with complete or very high stereochemical control. The hydroxymethyl group was converted into an aldehyde – which could be removed to give the tricyclic amine products that are unsubstituted at the ring junction positions – or was converted into an alkene, which allowed the formation of the core ring system of the alkaloids scandine and meloscine.

Asymmetric total synthesis of vindorosine, vindoline, and key vinblastine analogues.

Concise asymmetric total syntheses of vindoline (1) and vindorosine (2) are detailed based on a unique intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles inspired by the natural product structures. A chiral substituent on the tether linking the dienophile and oxadiazole was used to control the facial selectivity of the initiating Diels-Alder reaction and set the absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduced three rings and four C-C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural products in a single step. Implementation of the approach for the synthesis of 1 and 2 required the development of a ring expansion reaction to provide a 6-membered ring suitably functionalized for introduction of the Δ(6,7)-double bond found in the core structure of the natural products. Two unique approaches were developed that defined our use of a protected hydroxymethyl group as the substituent that controls the stereochemical course of the cycloaddition cascade. In the course of these studies, several analogues of vindoline were prepared containing deep-seated structural changes presently accessible only by total synthesis. These analogues, bearing key modifications at C6-C8, were incorporated into vinblastine analogues and used to probe the unusual importance (100-fold) and define the potential role of the vinblastine Δ(6,7)-double bond.

Asymmetric total synthesis of vindoline.

A concise asymmetric total synthesis of (-)-vindoline (1) is detailed based on a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which the tether linking the initiating dienophile and oxadiazole bears a chiral substituent that controls the facial selectivity of the initiating Diels-Alder reaction and sets absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduces three rings and four C-C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. Implementation of the approach also required the development of a unique ring expansion reaction to provide a six-membered ring suitably functionalized for introduction of the Delta (6, 7)-double bond found in the core structure of vindoline and defined our use of a protected hydroxymethyl group as the substituent used to control the stereochemical course of the cycloaddition cascade.

Cyclopropanecarbaldehyde with Two Protected Hydroxymethyl Groups.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cyclopropanecarbaldehyde with two protected hydroxymethyl groups

3,5-Dioxabicyclo[5.1.0]octane-8-carbaldehyde was synthesized in three steps, including initial stereoselective exo-cyclopropanation of 1,3-dioxacyclohept-5-ene with ethyl diazoacetate. The subsequent phosphorylation according to Abramov and Kabachnik-Fields gave the corresponding α-hydroxy(acetoxy)- and α-aminocyclopropylmethylphosphonates with protected hydroxymethyl moieties at the three-membered ring.

Highly Stereoselective Synthesis of Stereochemically Defined Polyhydroxylated Propargylamines by Alkynylation of N‐Benzylimines Derived from (R)‐Glyceraldehyde

AbstractThe addition of the lithium derivative of tert‐butyldimethylsilyl propargyl ether to N‐benzylimines derived from (R)‐2,3‐O‐isopropylideneglyceraldehyde has been achieved with acceptable yields and high diastereoselectivities. The syn/anti diastereoselectivity of the addition reaction can be controlled and reversed by the appropriate use of Lewis acids as imine precomplexing agents. Double stereodifferentiation processes using imines derived from (R)‐2,3‐O‐isopropylideneglyceraldehyde and (R)‐ or (S)‐α‐methylbenzylamine as starting materials occur with total stereocontrol to afford syn and anti vic‐propargylamino alcohol derivatives with orthogonally protected hydroxymethyl groups on both sides of the central core.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Preparation of New Chiral Building Blocks: Highly Enantioselective Reduction of Prochiral 1,3-Cycloalkanediones Possessing a Methyl Group and a Protected Hydroxymethyl Group at Their C2 Position with Baker's Yeast or CBS Catalyst

Highly enantioselective reduction of five-, six-, seven-, and eight-membered prochiral 1,3-cycloalkanediones possessing a methyl group and a protected hydroxymethyl group at their C2 position with baker's yeast or CBS catalyst and a new efficient and general method for preparing the 1,3-cycloalkanediones have been developed. These baker's yeast mediated reductions were found to produce corresponding ketols with high optical purity (>99% ee) and high yield. All of the prepared ketols and their derivatives, chiral building blocks, have been fully characterized, and their absolute configurations have been determined. These compounds would be useful for the convergent synthesis of complex natural products.

ChemInform Abstract: Conversion of the Carboxy Group of Sialic Acid Donors to a Protected Hydroxymethyl Group Yields an Efficient Reagent for the Synthesis of the Unnatural Beta‐Linkage.

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Conversion of the carboxy group of sialic acid donors to a protected hydroxymethyl group yields an efficient reagent for the synthesis of the unnatural beta-linkage

New sialyl donors with a protected hydroxymethyl group at the anomeric center are over 1000 times more reactive than the normal ester containing sialylation reagent and give excellent yield (>90%) with unusually high β-stereoselectivity in sialylation.

Synthese von funktionalisierten Bi(cyclopropylidenen)

Synthesis of Functionalized Bi(cyclopropylidenes) In view of the synthesis of attractive triafulvalene precursors 9, a series of bi(cyclopropylidenes) 8 with vinyl- (8a), alkoxycarbonyl (8c – f), hydroxymethyl (8h), as well as protected hydroxymethyl groups (8g, 8i) have been prepared by simple one-pot reactions of the corresponding 1,2-dibromo-cyclopropanes 6 with BuLi/CuCl2 at −95°. First experiments towards a direct low-temperature synthesis of bi(cyclopropylidenes) bearing good leaving groups 9k (X=AcO) and 9l (X=Br) are reported.

A total synthesis of (+)-pisiferol

A total synthesis of (+)-pisiferol (1) has been accomplished by utilising an optically active Wieland–Miescher ketone analogue (S)-(+)-(6) bearing an angular protected hydroxymethyl group, as the key intermediate. Reductive methylation of the monoacetal (7) of compound (6), followed by Huang–Minlon reduction, gives the trans-decalone acetal (9). Construction of the remaining carbocycle leading to the dodecahydrophenanthrenone (14) is achieved through five sequential reactions (deprotection, methoxycarbonylation, Michael addition with methyl vinyl ketone, demethoxycarbonylation, and intramolecular aldol cyclisation). After introduction of the 2-hydroxypropan-2-yl side-chain, dehydration followed by base-catalysed aromatisation affords pisiferol methoxymethyl ether (18). Finally, hydrolysis furnishes (+)-pisiferol (1).

The absolute stereochemistry of Wieland–Miescher ketone analogues bearing an angular protected hydroxymethyl group

The Wieland–Miescher ketone analogues (3) and (4), each bearing an angular protected hydroxymethyl group, have been prepared by the amino-acid catalysed cyclisation of their cyclohexane-1,3-dione derivatives (1) and (2); the optical purities and absolute configurations of (3) and (4) have been determined by applying the methoxy (trifluoromethyl)phenylacetate method and the c.d. exciton chirality method, respectively, to their mono-9-ol derivatives.

Synthesis of Wieland–Miescher ketone analogues bearing an angular protected hydroxymethyl group

Wieland–Miescher ketone analogues (1) and (2), bearing an angular protected hydroxymethyl group, have been prepared by alkylation of the lithiated methyl 2, 6-dimethoxycyclohexa-2, 5-diene-1-carboxylate.