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International audience; 3,4‐Dihydro‐2H‐pyrans are present in the skeletons of several natural products, and these versatile synthetic intermediates are readily transformed into tetrahydropyrans, pyridines, or 1,5‐dicarbonyl units. Among the strategies developed to access 3,4‐dihydro‐2H‐pyrans, the hetero‐Diels‐Alder reaction between an oxadiene and a dienophile is particularly valuable because up to three contiguous stereogenic centers can be created diastereo‐ and/or enantioselectively in a single step. This review addresses the mechanism of the reaction and presents methods for preparing the product dihydropyrans enantio‐ and diastereoselectively. Thermal and Lewis acid promoted cycloadditions are discussed, as is the role of activating groups on the oxadiene.

A new family of analogs of steganacin, an important antimitotic compound, was accessed. It takes advantage of a completely stereoselective sequence of two key steps. The central dihydropyrane core is built by a highly diastereoselective and facially controlled hetero-Diels–Alder reaction. It is followed by a nonphenolic biaryl oxidative coupling with a complete atropo-stereoselectivity. It leads to a quick way to form cyclic biaryl lignans.

A new practical approach to enantioenriched carboxy-differentiated aspartate derivatives was achieved in three steps via the 1,3-dipolar cycloaddition of N-benzyl-α-carbonyloxyethylnitrone with (R)-4-ethyl-N-vinyloxazolidin-2-one and chemoselective nucleophilic displacement of aspartimide under appropriate conditions (racemization less than 3%).

Asymmetric access to novel N-protected (di)peptidyl β3-aldehydes (“β3-PAs”) has been achieved through direct coupling of a chiral non-racemic 6-alkoxytetrahydrooxazinone with N-phthalyl L-α-amino acids. Kinetic resolution allows for the fruitful use of racemic amino acids in this process. Acidic hydrolysis of the diastereomerically pure, coupling products leads to the title N-phthalyl-β3-PAs in high yields. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Tren amine cations and carbonate anions adopt a ternary symmetry while tetra amine cations are tetrahedral. The symmetry of these constitutive ions influences strongly the nature of the solids which crystallise from solutions. Large fluorinated aluminate polyanions with tetrahedral symmetry appear in the presence of tren amine, while infinite chains of AlF6 octahedra are observed with tetra amine and that noncentrosymmetric structures are frequently encountered in rare earth fluoride carbonates.

For the first time, easily available N-(alpha-methoxyalkyl)amides were successfully used as synthetic equivalents of N-acylimines in an asymmetric heterocycloaddition process. The facial-controlled formation of 6-alkoxydihydrooxazines was thus achieved by SnCl(4)-promoted heterocycloaddition of (R)-O-vinyl pantolactone. By simple acidic hydrolysis of the crude heteroadducts, new beta-aryl- and beta-alkyl-substituted benzamido aldehydes were thus obtained in good overall yields with high enantioselectivities.

A high yielding, general, and practical procedure for the N-vinylation of 2-oxazolidinones via TMSOTf-promoted dehydroalkoxvlation of N,O-acetals is described.

N-Vinyloxazolidinone was conveniently prepared in 73% overall yield by an easy two-step procedure based on the dehydroalkoxylation of an intermediate hemiaminal using trimethylsilyl trifluoromethanesulfonate and triethylamine. The good dienophilicity of this enecarbamate was demonstrated in several [4+2] stereocontrolled processes involving activated 1-oxabutadienes under appropriate Lewis-acid catalyzed conditions. In addition, an unexpected amido-alkylation of the title compound is described under mild conditions.

The syntheses of the diaryls 14 and 21, substituted by two ω-cyanoalkyl chains (one on each ring), are described. Treatment of the unsymmetrical diaryl 14 with NaN(Me)Ph in a Thorpe-Ziegler reaction failed to give any definite product. Under the same conditions the symmetrical diaryl 21 led to an isomeric mixture of dimeric enaminonitriles 24. Mild acidic hydrolysis of the latter yielded the isomeric β-ketonitriles 25, whereas more drastic hydrolytic conditions led to the macrocyclic diketone 26.

[reaction: see text] The 1,3-oxazine route to enantiopure beta-amido aldehydes was investigated. Heterocycloaddition of the N-acyl imine 1 with (R)-O-vinylpantolactone provided the stable dihydroxazine 4c. High diastereocontrols were observed when using Yb(fod)3-catalyzed or SnCl4-mediated conditions, thus leading after quantitative hydrolysis to (R)-N-benzoyl-3-phenylpropanal with98% ee.

A high-yielding, practical two-step procedure for the preparation of N-benzylhydroxylamine starting from dibenzylamine is described. As specified in the detailed protocol, the reaction can be conveniently carried out on a > 0.5 mol laboratory scale.

International audience

(2′ R ,3 S ,4 S ,5 R )-(−)-Homoharringtonine 2 was synthesized by direct esterification of cephalotaxine, using the activatedforms of suitably substituted tetrahydropyrancarboxylic acids as sterically compact chiral side-chain precursors, followed by selective ring opening of the resulting (2′ R ,3 S ,4 S ,5 R )-(−)-anhydrohomoharringtonine 6 . Both enantiomers of the anhydro acyl moiety were prepared either by asymmetric α-hydroxyalkylation of the suitably substituted ethylenic α-ketoester 7 followed by acidic cyclisation, or by resolving the corresponding racemic mixture via formation of diastereomers with (−)-quinine. Racemic cephalotaxine, as well as both its enantiomers, were prepared from natural -partially racemized- (−)-cephalotaxine 1 .

Megacerotonic acid 1 has a highly exceptional structure, since it is probably the only γ-butyrolactone lignan in which the lactone ring is substituted by an aryl, an arylidene and a carboxy group. The structure of this lignan was confirmed by a racemic total synthesis which involved as key-steps a Stobbe condensation of the 3-arylglutaric ester 8 with p -anisaldehyde 9 , and the hydroxylation at C-4 of the intermediate 2,3-disubstituted glutaric ester 14 .

A systematic study of redox couples in fluoro acid medium has been carried out for the oxidative coupling of bisbenzocyclooctadiene lignan precursors. Tl2O3 and Re2O7 were found to be the more efficient reagents with precursors possessing methylenedioxy substituents for the former and only methoxy groups for the latter. Finally, oxidative coupling of a phenolic dibenzylbutane led to a mixture of two BBCOD's, resulting from para and ortho coupling to the phenolic group.

1,3-dipolar cycloadditions (1,3-DC) reactions involving nitrones as dipole have met a recent growing interest 1 – 8 especially in their diastereoselective and enantioselective versions. 9 - 10 This...

Efficient access to masked β-amino-aldehydes was performed starting from 6-alcoxy tetrahydrooxazinone 6a–d (6-ATO). Transacetalization leads to the opening of the cycle to form either unsymmetric acetal 7 or symmetric acetals 16–18. These amino acetals are key compounds, obtained with 99% ee, which can be engaged in efficient peptide coupling. This method could easily provide peptides aldehydes or small amido aldehydes as exemplified with the formal synthesis of ent-Maraviroc.

1,3-dipolar cycloadditions (1,3-DC) reactions involving nitrones as dipole have met a recent growing interest 1 – 8 especially in their diastereoselective and enantioselective versions. 9 - 10 This...

The structure of the unusual neolignan megacerotonic acid 2 was confirmed by a racemic total synthesis which involved, as a key-step, the hydroxylation at C-4 of the 2,3-disubstituted glutaric ester 9.

The total synthesis of the racemic furano bisbenzocycloheptene 3 is described. The compound 3, which contains five asymmetric centres, is the 5,8-bis-epimer of the tetra- O -methyl derivative of metasequirin-B (1), a norcycloneolignan of unusual structure.

Cycloaddition reactions occupy a special place in organic synthesis because of the simultaneous creation of several bonds and generation of new stereogenic centers in often highly stereocontrolled ...

The reaction between octadecyl 3-(3,5-di- tert -4-hydroxyphenyl)propanoate and dibasic lead stearate, two compounds added in most PVC formulations, has been investigated in bulk. The structure of the resulting product, obtained after a one-pot synthesis, was characterized by HRMS and 2D NMR analyses. The product of empirical formula C 70 H 116 O 7 has been identified as an unknown highly substituted furan. The reaction mechanism between both products to produce this original furan has been established. The first step leads to a discoloured lead IV complex with bis-quinonemethide. The second step consist of a hydrolysis during the solvent extractions or under UV exposure leading to a tetrasubstituted furan.

A systematic study of oxidants used in fluoro acid medium allowed us to increase notably the number of efficient reagents for the non-phenolic oxidative coupling of lignan and alkaloid precursors. If dibenzylbutanolide had no methylenedioxyle group, Re 2 O 7 and RuO 2 .2H 2 O were the most efficient. With a methylenedioxyle group, best results were obtained with Tl 2 O 3 , Mn(OAc) 3 .2H 2 O and Ce(OH) 4 . Finally, aporphines were obtained with good yields with Ce(OH) 4 , RuO 2 .2H 2 O and Fe(OH)(OAc) 2 .

The 1,3-oxazine route to enantiopure β-amido aldehydes was investigated. Heterocycloaddition of the N-acyl imine 1 with (R)-O-vinylpantolactone provided the stable dihydroxazine 4c. High diastereocontrols were observed when using Yb(fod)3-catalyzed or SnCl4-mediated conditions, thus leading after quantitative hydrolysis to (R)-N-benzoyl-3-phenylpropanal with >98% ee.

Amino acid derived nitrones were conveniently synthesized in good-to-excellent yields by condensation of α-ketoesters with N-benzylhydroxylamine. The cycloaddition reactions of these nitrones with different alkenes were investigated under thermal solvent-free conditions. Considering conversions, yields, and selectivities, alkyl vinyl ethers have proven to be valuable partners to achieve this transformation, which creates a tetrafunctionalized stereogenic quaternary center. From the adducts derived from vinyl ethers, a three-step access to highly functionalized α-substituted amino acid derivatives is described.

N-Vinyloxazolidinone was conveniently prepared in 73% overall yield by an easy two-step procedure based on the dehydroalkoxylation of an intermediate hemiaminal using trimethylsilyl trifluoromethanesulfonate and triethylamine. The good dienophilicity of this enecarbamate was demonstrated in several [4+2] stereocontrolled processes involving activated 1-oxabutadienes under appropriate Lewis-acid catalyzed conditions. In addition, an unexpected amido-alkylation of the title compound is described under mild conditions.

N-(β,β-Difluorovinyl)oxazolidin-2-ones were conveniently prepared in good yields in two steps from the parent oxazo-lidin-2-ones. The [3+2]- and [4+2]-cycloaddition-type reactions with electron-deficient partners were investigated as first application of these new enamides. TMSOTf was efficient in promoting these two reactions, and the corresponding heterocyclic difluoro adducts were obtained in high yields.

Amino acid derived nitrones were conveniently synthesized in good-to-excellent yields by condensation of alpha-ketoesters with N-benzylhydroxylamine. The cycloaddition reactions of these nitrones with different alkenes were investigated under thermal solvent-free conditions. Considering conversions, yields, and selectivities, alkyl vinyl ethers have proven to be valuable partners to achieve this transformation, which creates a tetrafunctionalized stereogenic quaternary center. From the adducts derived from vinyl ethers, a three-step access to highly functionalized alpha-substituted amino acid derivatives is described.

Cycloaddition reactions occupy a special place in organic synthesis because of the simultaneous creation of several bonds and generation of new stereogenic centers in often highly stereocontrolled ...

(−)-α-Conidendrin 1 was synthesized according to a general reactionscheme that could be applied to other retrolignans as well. Thus, treatment of the optically active β-benzyl-γ-butyrolactone ( R )-(+)- 4 with NBS, followed with benzyl alcohol, selectively introduced a benzyloxy group in the benzylic position and afforded the mixture of epimers 7 . α-Alkylation of the lithium enolate of the corresponding silyl ethers 10 , with O -benzylvanillyl bromide 11 , gave the trans disubstituted lactones 13 (2 epimers). Catalytic hydrogenolysis (Pd-C) of 13 selectively split the aryl benzyl ether linkage, and gave the compounds 14 . Intramolecular Friedel-Crafts cyclization of the latter, using the benzyloxy group as the leaving group, was induced with BF 3 -Et 2 O and afforded (−)-α-conidendrin 1 in 36% overall yield from methyl α-vanillylhemis uccinate ( R )-(+)- 17 .

Resume Racemic and optically active α,β-dibenzyl-γ-butyrolactones (of synthetic origin) were hydroxylated in the α position with respect to the carbonyl group, using oxygen in the presence of LHDS. This led to (−)-trachelogenin 1 , (−)-nortrachelogenin 2 and (+)-wikstromol 3 , whose interesting pharmacological properties were recently described. These natural lignans were correlated to (±)-methyltrachelogenin 12 whose relative structure was definitely established by X-ray cristallography.

N-benzyl aspartate nitrones 2, prepared by addition of N-benzylhydroxylamine to dialkyl acetylenedicarboxylates 1, underwent [3 + 2] thermal cycloaddition with a wide range of alkenes to afford isoxazolidines 4 bearing a polyfunctionalized quaternary center. Under these uncatalyzed conditions, the trans stereocontrol observed with vinyl ethers is higher than that obtained with all acyclic activated nitrones reported to date. The first asymmetric access to a type-4 pure adduct was achieved starting from the chiral aspartate nitrone derived from (S)-alpha-methylbenzylhydroxylamine.

N-(β,β-Difluorovinyl)oxazolidin-2-ones were conveniently prepared in good yields in two steps from the parent oxazo-lidin-2-ones. The [3+2]- and [4+2]-cycloaddition-type reactions with electron-deficient partners were investigated as first application of these new enamides. TMSOTf was efficient in promoting these two reactions, and the corresponding heterocyclic difluoro adducts were obtained in high yields.

Resolution of methyl α-(3,4,5-trimethoxybenzyl) hemisuccinate, (R,S)-2, by means of (−)-ephedrine, followed by Ca(BH 4 ) 2 reduction, afforded (R)−(+)-β-(3,4,5-trimethoxybenzyl) butanolide. This lactone was used as a starting material for the asymmetric syntheses of eight recently discovered lignans belonging to, or deriving from, the α,β-dibenzylbutanolide series, such as cubebinone and dihydroclusin

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) was conveniently used to promote the reaction involving N-alkenyloxazolidin-2-ones and activated nitrones, leading to new 4-substituted 5-azaisoxazolidines in good to excellent yields. This TMSOTf-promoted procedure expanded the scope of reaction of N-vinyloxazolidin-2-ones and nitrones in complementary way to the corresponding classical 1,3-dipolar cycloaddition. Some of these adducts could not be obtained under thermal activation.

New isoxazolidines were synthesized in good to excellent yields by 1,3-dipolar cycloaddition of N-vinylamide dipolarophiles and nitrones. Strikingly, solvent-free conditions gave high conversion and yields, shortened reaction time, and minimized degradation products. N-Vinyloxazolidin-2-one and its analogues used in these cycloaddition reactions were conveniently prepared in excellent yields by a modified version of Buchwald's one-step copper-catalyzed vinylation using vinyl bromide. From the adducts, a two-step access to various unsymmetric aspartate derivatives was also described.

N-benzyl aspartate nitrones 2, prepared by addition of N-benzylhydroxylamine to dialkyl acetylenedicarboxylates 1, underwent [3 + 2] thermal cycloaddition with a wide range of alkenes to afford isoxazolidines 4 bearing a polyfunctionalized quaternary center. Under these uncatalyzed conditions, the trans stereocontrol observed with vinyl ethers is higher than that obtained with all acyclic activated nitrones reported to date. The first asymmetric access to a type-4 pure adduct was achieved starting from the chiral aspartate nitrone derived from (S)-alpha-methylbenzylhydroxylamine.

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The [4 + 2] acido-catalyzed heterocycloaddition between new beta-substituted N-vinyl-1,3-oxazolidin-2-ones (with R' = Me, Ar, CH2 Ar) and beta,gamma-unsaturated alpha-ketoesters (R = Ar) afforded heteroadducts with high levels of endo and facial selectivities. A complete reversal of facial differentiation was achieved by varying the Lewis acid, leading to the stereoselective formation of either endo-alpha or endo-beta adducts. [reaction: see text].

Under Lewis acid conditions, reaction of N -Boc, O -Me acetals with the ( R )-(+)- O -vinyl-pantolactone does not lead to the expected dihydrooxazine, but to the corresponding tetrahydrooxazinone, as a result of the loss of the t -Bu group. A diastereoselective and asymmetrical way to these new heterocyclic compounds is described, together with the first evidence of their ability to undergo N -acylation.

Under smooth Eu(fod)(3)-catalyzed conditions, the inverse-electron demand hetero-Diels-Alder reactions between enantiopure N-vinyl-2-oxazolidinones 1a-f and representative beta,gamma-unsaturated alpha-ketoesters proceed with a high degree of endo and facial diastereoselectivity. The elucidation of the stereostructure of these adducts, performed by X-ray analysis or chemical correlation, shows that the endo-selective cycloaddition process is facially controlled in favor of the (2S,4S)-adduct when starting from a (4S)-dienophile or vice versa. The specific interest of the adducts 10a-e, derived from (E)-4-tert-butoxymethylene pyruvic acid methyl ester 9, has been exemplified by the two-step and highly stereoselective transformation of these adducts into the new and valuable N-2-deoxyglycosyl-oxazolidinones 12a-e, isolated in a pure diastereo- and enantiomeric form.

A high yielding, general, and practical procedure for the N-vinylation of 2-oxazolidinones via TMSOTf-promoted dehydroalkoxvlation of N,O-acetals is described.

Regioselective introduction of a benzoxy group, in the benzylic position of the β-benzyl-γ-butyrolactone (R)-(+)-8, was achieved by tretment with NBS followed with benzyl alcohol. α-Alkylation of the lithium enolate of the resulting intermediate 11, with O -benzylvanillyl bromide 5, gave the trans disubstituted lactone 13. Catalytic hydrogenolysis (PdC) of 13 selectively split the aryl benzyl ether linkage, thus giving the compound 14. Intramolecular Friedel-Crafts cyclisation of the latter, using the benzoxy group as the leaving group, was induced with BF3. Et2O and afforded high yields of (−)-α-conidendrin 2.