Asymmetric cyclopentannelation. Chiral auxiliary on the allene

An enantioselective variant of the synthesis of cross-conjugated cyclopentenones, based on D-glucose-derived chiral auxiliaries, is described. Minor modification of the method makes it applicable to the preparation of both enantiomeric series of products. Both enantiomers of the key intermediate in our roseophilin synthesis have been prepared.     

A camphor-derived chiral auxiliary for hydroxyalkyl radicals

A new camphor-derived chiral auxiliary for hydroxyalkyl radicals is described. The auxiliary is prepared by the Baeyer–Villiger oxidation of 3-fluorocamphor 12 to give lactone 14, followed by its reduction to the lactol 16. Compound 16 is converted to the acetal–ester 17 and then on to radical precursor 18. A key feature of this auxiliary is the incorporation of a fluorine atom at C-3 (pyranoside numbering), which accelerates the Baeyer–Villiger reaction, results in complete anomeric control during auxiliary attachment, and stabilizes the resulting acetal center. The chiral radical derived from carboxylic acid 18 adds to methyl 2-trifluoroacetoxyacrylate to give adducts 22 and 23 with good diastereocontrol (ds from 3:1 at 0°C up to 4.5:1 at −78°C).     

CamTHP*OH: a camphor-derived delta-lactol auxiliary for the effective desymmetrization of attached glycinamide residues. Asymmetric synthesis of alpha-amino carbonyl compounds

Stereoselective allylation of camphor and subsequent terminal hydroformylation affords a new delta-lactol auxiliary (camTHP*OH) on multigram scale. Stereoselective condensation with glycine dimethylamide and Cbz protection affords a camTHP*-desymmetrized glycinamide building block which undergoes efficient and highly diastereoselective metal enolate alkylation reactions. Acid-mediated deprotection affords the N-Cbz-protected alpha-amino amide products which may be converted directly to alpha-amino ketones on treatment with Grignard or organolithium reagents without loss of stereochemical integrity. [reaction: see text]     

Asymmetric Pauson-Khand reactions using camphor-derived chelating thiols as chiral controllers

A convenient procedure for the preparation of enantiopure 10-(R-thio)-2-exo-bornanethiols from (1S)-camphor-10-thiol has been developed. The ethynyl derivatives of these thiols gave excellent diastereoselectivities (up to 98:2) in Pauson-Khand reactions with norbornene and norbornadiene through the intermediacy of a chelated dicobalt pentacarbonyl complex. Thermal reaction conditions starting from the preformed chelated complex gave better results than N-oxide-promoted runs with in situ generation of the chelated intermediate. The corresponding adducts have been elaborated through a protocol consisting of conjugate addition, samarium iodide-promoted cleavage of the chiral auxiliary, and retro-Diels-Alder reaction to afford 4-substituted 2-cyclopentenones in high enantiomeric purity.     

Light-induced coumarin cyclopentannelation

[reaction: see text] Whereas cyclopentenylcarbenes resulting from photocycloaddition of 4-alk-1-ynylcoumarins to 2,3-dimethylbut-2-ene undergo tandem cyclization to hitherto unknown tetracyclic (4-hetera)cyclopent[b,c]acenaphthylenes, the corresponding cyclopentenylnitrenes stemming from 4-cyanocoumarins and the same alkene are converted into tricyclic imines via H-abstraction.     

Convergent cyclopentannelation process

[reaction: see text] A triply convergent synthesis of alpha-methylene cyclopentenones has been demonstrated in which an intermediate C,O-dianion is formed and trapped on carbon by electrophiles.     

A cationic cyclopentannelation

The alkoxyallene adducts of $\text{O}$-trimethylsilyl hydroxymethylene ketones undergo a facile acid catalyzed cyclization to produce functionalized cyclopentenones in high yield.     

Asymmetric addition of diethylzinc to aldehydes catalyzed by a camphor-derived β-amino alcohol

The asymmetric addition of diethylzinc to aromatic and aliphatic aldehydes, including linear aliphatic ones, catalyzed by 2 mol % of β-amino alcohol (1S, 2R)-7,7-dimethyl-1-morpholin-4-yl-bicyclo[2.2.1]heptan-2-ol 10 gave the corresponding secondary alcohols in high yields and with up to 94% ee at ambient temperature after 15 min.     

Asymmetric iodolactamization induced by chiral oxazolidine auxiliary

Asymmetric iodolactamization reactions of unsaturated amides with oxazolidines as the chiral auxiliaries were investigated. With (4S)-4-((2R)-2-butyl)-2,2-dimethyloxazolidine as the auxiliary and LiH as the base, a number of unsaturated amides underwent iodolactamization smoothly to afford the corresponding gamma- and delta-lactams in 30-98% yield with de values up to 97%.     

Enantioselective epoxidation by the chiral auxiliary approach: Asymmetric total synthesis of (+)-Ambrisentan

Enantioselective and a highly concise total synthesis of Ambrisentan are described. The chiral auxiliary controlled enantioselective epoxidation (Azerad protocol), photochemical regioselective epoxide opening, and base mediated ester hydrolysis reactions are the key reactions.     

Asymmetric synthesis of sulfinamides using (-)-quinine as chiral auxiliary

A process has been designed and demonstrated for the asymmetric synthesis of sulfinamides using quinine as auxiliary. A variety of chiral sulfinamides including N-alkyl sulfinamides with diverse structure were prepared in good yields and excellent enantioselectivity starting from easily available and inexpensive reagents. The auxiliary quinine could be recovered and recycled.     

A formal total synthesis of roseophilin: cyclopentannelation approach to the macrocyclic core

[formula: see text] The formal total synthesis of the macrocyclic core of roseophilin 4 has been accomplished in 12 steps from 5-hexenal 8. The cyclopentannelation reaction was used to form the aliphatic five-membered ring of 3. Diene 2 was assembled by means of a Stetter reaction. Ring-closing metathesis of 2, reduction, and Knorr reaction of the 1,4-diketone 5 gave the ketopyrrole 3.     

Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy

An asymmetric eight-step total synthesis of (20S)-camptothecin, starting from the known compound tert-butyl (2-chloroquinolin-3-yl)methylcarbamate, is described. A Heck reaction followed by an intramolecular Michael addition to form the C-ring provides the first key step in this synthesis. The construction of the 20(S) chiral center relies on a chiral auxiliary-mediated Michael addition using (2R,5R)-2-tert-butyl-5-ethyl-1,3-dioxolan-4-one as the auxiliary.     

Asymmetric intermolecular Pauson-Khand reactions of unstrained olefins: the (o-dimethylamino)phenylsulfinyl group as an efficient chiral auxiliary

The first asymmetric version of intermolecular Pauson-Khand reactions of unstrained alkenes is described. Generally simple acyclic alkenes exhibit low reactivity and regioselectivity in intermolecular Pauson-Khand reactions; however, o-(dimethylamino)phenyl vinyl sulfoxide reacts under very mild conditions with a wide variety of terminal alkynes in a completely regioselective and highly stereoselective manner. The utility of the resulting 5-sulfinyl-2-cyclopentenones in asymmetric synthesis is illustrated by a very short enantioselective synthesis of the antibiotic (-)-pentenomycin I.     

Asymmetric 1,3-dipolar cycloaddition of nitrile oxides to chiral acryloyl esters bearing glucofuranose as auxiliary

Asymmetric 1,3-dipolar cydoaddition of nitrite oxides to an acryloyl ester (1) derived from 1,2:5,6-di-O-isopropylidene glucose (6) was studied. Solvent and temperature effect was discussed. The single diastereoisomer was isolated with high diastereoselective excess.     

Novel platinum-catalysed cascade reactions: cyclisation, ring expansion and 1,2-oxygen shift reaction of a camphor-derived diyne

2,3-Bis(ethynyl)-3-hydroxy-camphorsultam was converted in one step into a novel tetracyclic cyclopentenone derivative, in an unprecedented platinum-catalysed cascade reaction. In the course of this reaction, cyclisation of the alkynes takes place, together with a ring expansion of the camphor skeleton and 1,2-migration of an oxygen atom. The structure of the unexpected product was analysed in detail by one- and two-dimensional NMR spectroscopy, and validated with the help of quantum mechanical calculations (B3LYP/6-31G^∗∗ and B3LYP/6-31+G(2df)) of the IR vibrational frequencies and the ¹H and ¹³C isotropic chemical shifts.     

Renewable camphor-derived hydroperoxide: synthesis and use in the asymmetric epoxidation of allylic alcohols

Renewable enantiopure tertiary furyl hydroperoxide has been easily synthesized in two steps starting from low cost (+)-(1R)-camphor and it has been used in the asymmetric epoxidation and kinetic resolution of allylic alcohols (enantioselectivities up to 46%).     

Asymmetric aldol reactions using chiral CF3-Oxazolidines (Fox) as chiral auxiliary

The aldol reactions of amide enolates derived from a trifluoromethylated oxazolidine (Fox) chiral auxiliary occur in good yields with a moderate anti diastereoselectivity (Li and Na enolates) to a high syn diastereoselectivity (boron enolate). After removal, the Fox chiral auxiliary is very conveniently and efficiently recovered in basic conditions.     

Mechanistic subtleties in the cyclopentannelation of allenolate allyl carbamates: the origin of the center-to-center chirality transfer

The stereospecific rearrangement of allene carbamates i to alkylidenecyclopentenones iii is concerted, displays charge donation from the pi*(allenonate) to the sigma*(C-leaving group), and shows mechanistic features of both pericyclic and ionic processes, modulated in part by the degree of ionic interaction (O-...Li+) in the putative intermediate allenolate ii.     

A camphor-derived vinylsulfonium salt as a reagent for a cycloannulation

A chiral, non-racemic vinylsulfonium salt 6 was prepared from camphorquinone in seven steps and reacted with indole-2-carboxaldehyde to give a tricyclic azido alcohol 2 in a 35% yield and 43% e.e. and a 40% recovery of the chiral sulfide.