Enantiodivergent synthesis of cytotoxic styryl lactones from d-xylose. The first total synthesis of (+)- and (−)-crassalactone C

Enantiodivergent total syntheses of both (+)- and (−)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C have been accomplished starting from d-xylose. The key steps of the synthesis of 7-epi-(+)-goniofufurone were a stereo-selective addition of phenyl magnesium bromide to a protected dialdose, and a stereospecific furano-lactone ring formation by reaction of a related hemiacetal derivative with Meldrum's acid. Synthesis of both (+)-goniofufurone and (+)-crassalactone C required a configurational inversion at C-5 in the common intermediate that was efficiently achieved under the standard Mitsunobu conditions, or alternatively through a sequential oxidation of the benzylic hydroxyl group followed by a stereo-selective reduction with borohydride. A similar approach was then applied to the synthesis of the unnatural (−)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C, as well as two novel, conformationally constrained analogues of both (+)- and (−)-goniofufurone. Their in vitro antiproliferative activities against a number of human tumour cell lines were recorded and compared with those observed for the parent natural products.     

A concise synthesis of (+)-goniofufurone, (+)-7-epi-goniofufurone, (+)-crassalactones B and C

The concise and efficient synthesis of (+)-goniofufurone, (+)-7-epi-goniofufurone, (+)-crassalactones B and C were achieved in 6 to 7 steps from the known d-glucono-δ-lactone derivative 9. An acid-mediated cascade cyclization was employed to construct the furanofurone bicyclic framework in one-pot.     

Novel goniofufurone and 7-epi-goniofufurone mimics from an unexpected titanium-mediated displacement process

Treatment of 7-O-benzoyl-5-O-benzyl derivatives of (+)-goniofufurone or 7-epi-(+)-goniofufurone with titanium(IV) chloride or titanium(IV) bromide gave 7-chloro and 7-bromo-7-deoxy-goniofufurone mimics as the main reaction products along with minor amounts of the corresponding C-7 epimers. An unexpected cyclized product, benzoxepane 8 was isolated in some cases.     

Concise stereoselective synthesis of marine sesterterpene, 16-deacetoxy-12-epi-scalarafuran acetate and its 14-epimer via intramolecular Diels-Alder addition

The stereoselective synthesis of C12 oxygenated marine scalaranic sesterterpene 16-deacetoxy-12-epi-scalarafuran acetate and its 14-epimer were described. A highly stereoselective intramolecular Diels-Alder addition was designed as the key step to construct the ring D, and the absolute configurations of natural 16-deacetoxy-12-epi-scalarafuran acetate was supported by the X-ray diffraction analysis of single crystal of corresponding 16-deacetoxy-12-epi-scalarafuran.     

Stereoselective total synthesis of (+)-boronolide, (+)-anamarine, 8-epi-spicegerolide

A stereoselective total synthesis of the naturally occurring cytotoxic lactones (+)-boronolide, (+)-anamarine, and 8-epi-spicigerolide is described. d-Xylose has been used as a chiral source to construct the four contiguous oxygenated stereogenic centers of target molecules. The diastereoselective allylation was performed using Brown’s protocol and the lactone moiety was prepared by ring closing metathesis.     

An asymmetric approach to 5-O-carbamoyl-2-epi-polyoxamic acid and the total synthesis of 2′′-epi-polyoxin J

A stereospecific synthetic approach to 5-O-carbamoyl-2-epi-polyoxamic acid has been developed. The asymmetric nucleophilic addition of 2-lithiofuran to a tert-butanesulfinyl imine was employed as the key step to construct the C-2 stereocenter and 2′′-epi-polyoxin J has been synthesized for the first time. Significantly, the synthesis provides a facile method for the large scale and stereoselective preparation of 5-O-carbamoyl-2-epi-polyoxamic acid and some related diastereoisomers of polyoxins and its analogues because of its simple operation, excellent yield, and high stereoselectivity. This will be convenient for research of the polyoxins’ structure–activity relationship and to search for more potent and effective anticandidal agents.     

Asymmetric total synthesis of (+)-gabosine C and (+)-4-epi-gabosine J using acetate migration and RCM reaction

A concise, unified and stereoselective total synthesis of (+)-gabosine C and (+)-4-epi-gabosine J from a common polyhydroxylated cyclohexenol intermediate which was synthesized from readily available D-ribose has been described. The synthetic avenue includes stereoselective Grignard reaction, silyl ether deprotection followed by acetate migration, RCM reaction, oxidative diol cleavage, hydroxymethylation and oxidative rearrangement as key steps.     

The combined use of stereoelectronic control and ring closing metathesis for the synthesis of (−)-8-epi-swainsonine

A novel and efficient synthesis of (−)-8-epi-swainsonine 2 is reported. Stereocontrolled diol formation from the bicyclic alkene 3 followed by a stereoselective vinylation of the aldehyde and ring closing metathesis gave the indolizidine ring system, which was converted into (−)-8-epi-swainsonine 2.     

Stereoselective synthesis of (−)-8-epi-swainsonine starting with a chiral aziridine

An efficient synthesis of (?)-8-epi-swainsonine, starting from a commercially available 1-(R)-α-methylbenzylaziridine-2-methanol, was developed. The synthetic route utilizes stereocontrolled Sharpless asymmetric dihydroxylation governed by AD-mix-β followed by an aziridine ring opening-cyclization sequence to generate the five membered N-heterocyclic ring system present in the bicyclic target. A subsequent stereoselective allylation and piperidine ring forming cyclization then produced a precursor that was converted into (?)-8-epi-swainsonine.     

Nucleophilic additions of trimethylsilyl cyanide to cyclic oxocarbenium ions: evidence for the loss of stereoselectivity at the limits of diffusion control

The limitations of stereoelectronic models in assessing the stereoselective nucleophilic substitution reactions of cyclic oxocarbenium ions at high reaction rates are discussed. Evidence is provided suggesting that the diastereoselectivity of nucleophilic substitution reactions is attenuated at the limits of diffusion control. The low diastereoselectivities observed in the reactions of trimethylsilyl cyanide with five- and six-membered ring oxocarbenium ions are attributed to the high reactivity of the nucleophile and its reactions with these electrophiles at diffusion control rates.     

Stereoselective Syntheses of all the Possible Stereoisomers of Coronafacic Acid

An efficient and stereoselective syntheses of all the possible stereoisomers of coronafacic acid (CFA) has been developed. The stereochemistries of C3a and C7a were controlled in a diastereoselective Diels-Alder type cycloaddition using a chiral auxiliary. CFA and 6-epi-CFA were synthesized by hydrogenation of a common intermediate. During the synthesis of 6-epi-CFA, we established that its cis-fused configuration is important for the introduction of C4-C5 double bond by dehydration. This report is the first practical synthesis of both 6-epi-CFA, and its enantiomer.     

High 1,3-trans stereoselectivity in nucleophilic substitution at the anomeric position and β-fragmentation of the primary alkoxyl radical in 3-amino-3-deoxy-ribofuranose derivatives: application to the synthesis of 2-epi-(-)-jaspine B

The high inverse stereoselectivity in the nucleophilic substitution at the anomeric position of 3-amino-3-deoxy-ribofuranose derivatives is reported. This unprecedented stereoselectivity is explained in terms of preferential nucleophilic attack on the "inside face" of the respective five-membered ring oxocarbenium ion that orients pseudoequatorially to the benzylamine group placed at the C-3 position. In addition, an unusual β-fragmentation of a primary alkoxyl radical generated from its corresponding N-phthalimide derivative was achieved, and thus taking advantages of both reactions, the total synthesis of 2-epi-(-)-jaspine B was completed.     

Total synthesis of 2-(2-hydroxyalkyl)-piperidine alkaloids (−)-halosaline and (−)-8-epi-halosaline via iterative asymmetric allylation/RCM strategy

Total synthesis of 2-(2-hydroxyalkyl)-piperidine alkaloids, (?)-halosaline and (?)-8-epi-halosaline is reported from n-butyraldehyde using iterative asymmetric allylation, nucleophilic substitution with an azide and ring-closing metathesis as the key reactions.     

Cover Feature: Stereoselective Domino Semipinacol-Schmidt Reaction: Diastereoselective Synthesis of 7 a-epi-(+)-Lepadiformine C and Formal Synthesis of 7 a-epi-(−)-Lepadiformine A (Eur. J. Org. Chem. 19/2023)

A concise approach has been developed for the diastereoselective synthesis of the azatricyclic core of (−)-7 a-epi-lepadiformine A ( 8 a ) and (−)-7 a-epi-lepadiformine C ( 8 b ) using stereoselective domino semipinacol-Schmidt reaction as a key step. In presence of TiCl₄, the oxaspiropentane-azide derivatives underwent stereoselective domino cyclization to furnish the corresponding angularly fused azatricyclic cores in very good yields. Moreover, azatricyclic core of (−)-7 a-epi-lepadiformine A has also been realized, in a stepwise manner, through the intramolecular Schmidt reaction of azido-spirocyclobutanone intermediate. The synthetic utility of domino semipinacol-Schmidt reaction is further shown in the diastereoselective synthesis of (+)-7 a-epi-lepadiformine C ( 7 ).     

Synthesis of (+)-altholactone, (+)-7-epi-altholactone, (−)-etharvensin,and (+)-alumheptolide-A using Pd-catalyzed carbonylation

Syntheses of (+)-altholactone isolated from Goniothalamus giganteus and its C-7 epimer (+)-7-epi-altholactone, (?)-etharvensin and (+)-alumheptolide-A were achieved. The lactone ring of these compounds was constructed using Pd-catalyzed carbonylation.     

Using nucleophilic substitution reactions to understand how a remote alkyl or alkoxy substituent influences the conformation of eight-membered ring oxocarbenium ions

[reaction: see text] A remote alkoxy substituent strongly stabilizes one particular conformer of an eight-membered ring oxocarbenium ion by a through-space electrostatic effect. X-ray crystallographic analysis of a crystalline derivative proves that kinetically controlled nucleophilic substitution favors the 1,4-trans product. Nucleophilic substitution of the corresponding alkyl-substituted acetate, however, is unselective. A computational model has been developed and experimentally validated to predict the low-energy conformers of C3-, C4-, or C5-alkyl- or alkoxy-substituted eight-membered ring oxocarbenium ions.     

A short stereoselective synthesis of the protected uracil 3′-epi-polyoxin C

A short synthetic approach to the protected uracil 3′-epi-polyoxin C 20 has been developed. The stereoselective [3,3]-sigmatropic rearrangement of the corresponding 7-thiocyanato-α-d-xylo-hept-5-enfuranose 6 was employed as the key step to construct the C-5 stereocentre in 5-isothiocyanato-α-d-gluco-hept-6-enfuranose 8 and the formal synthesis of uracil 3′-epi-polyoxin C has been accomplished for the first time. This synthesis provides a facile method for multigram scale preparation and thus is useful for the research into the polyoxins’ structure-activity relationship and to search for more potent and effective anticandidal agents.     

New asymmetric strategy for the total synthesis of naturally occurring (+)-alexine and (−)-7-epi-alexine

A novel and highly convenient process is described for the asymmetric synthesis of polyhydroxylated pyrrolizidine alkaloids, (+)-alexine [(1R,2R,3R,7S,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine] and (−)-7-epi-alexine [(1R,2R,3R,7R,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], as the potent glycosidase inhibitors by featuring the efficient and stereodefined elaboration of the functionalized pyrrolidine derivatives, which were, in turn, prepared via stereoselective manipulation of the homochiral allyl alcohol precursors derived from l-xylose.     

Synthesis of dysiherbaine analogue

Synthesis of dysiherbaine analogue 4, which corresponds to 8,9-epi-neodysiherbaine A, is described. The synthesis features a concise route to the bicyclic ether skeleton through stereoselective C-glycosylation to set the C₆ stereocenter and 5-exo ring-closure to form the tetrahydrofuran ring. The results of preliminary biological studies of 4 are also provided.     

Stereoselective syntheses of 20-epi cholanic acid derivatives from 16-dehydropregnenolone acetate

A stereoselective total synthesis of naturally occurring 20-epi cholanic acid derivatives has been realized, starting from readily available 16-dehydropregnenolone acetate. The key step of these syntheses involves an ionic hydrogenation of a C-20,22-ketene dithioacetal and deoxygenation of steroidal C-20 tert-alcohols, to set up the unnatural C(20R) configuration with 100% stereoselectivity. The unnatural C-22 aldehydes with C(20R) stereocenters thus obtained were elaborated to 20-epi cholanic acid derivatives. Two derivatives of 20-epi cholanic acid were synthesized and their structures have been confirmed by single crystal X-ray analysis. Catalytic hydrogenation of 16-dehydropregnenolone acetate and 16-dehydropregnenolone in ethanol affords C-5,C-16 tetrahydro products. Crystal structure analysis of one of these products revealed C-5α and C-17α configurations of the hydrogen atoms.