Domino intramolecular enyne metathesis/cross metathesis approach to the xanthanolides. Enantioselective synthesis of (+)-8-epi-xanthatin

The first total synthesis of (+)-8-epi-xanthatin (1) has been achieved in 14 steps starting from the commercially available ester 24, which was converted into aldehyde 23 in six steps. An enantioselective aldol reaction of 23 gave 30, which was transformed into triflate 22 in four steps, setting the stage for a palladium-catalyzed carbonylation reaction to form acrylate 34. Compound 34 was then subjected to a deprotection/lactonization sequence to furnish enyne 21, which underwent a domino enyne ring-closing metathesis/cross metathesis process to form a seven-membered carbocycle and (E)-conjugated dienone, thereby completing the synthesis of 1. This domino ruthenium-catalyzed metathesis reaction thus serves as an efficient method to construct the core of xanthanolide and other sesquiterpene lactones.     

Studies directed towards the stereoselective total synthesis of ilexlactone via a tandem ring-closing enyne metathesis protocol

Studies directed towards the stereoselective total synthesis of ilexlactone resulted in the synthesis of bicyclic systems 1a, 1b and ent-1a through tandem ring-closing enyne metathesis using Grubbs’ catalyst. The structures of synthetic 1a, 1b and ent-1a revealed that the proposed structure for ilexlactone is incorrect.     

Synthesis and determination of absolute configuration of tetracetate 4a-carba-d-xylofuranoside

The synthesis of carbasugar analogue tetracetate 4a-carba-d-xylofuranoside (1) was reported. The new route involved the conversion of d-(−)-tartatic acid into an enyne compound, which was then cyclized via a key ring-closing enyne metathesis to form the key intermediate 1-vinyl cyclopentene 9, which was then stereoselectively converted to our target. The absolute configuration of the enyne was determined by modified Mosher's method, while that of tetracetate 4a-carba-d-xylofuranoside by ROSEY spectroscopy and γ-gauche effect.     

Stereoselective synthesis of (6S) and (6R)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one and their cytotoxic activity against cancer cell lines

Stereoselective total synthesis of α,β-unsaturated lactone (1a), isolated from Ravensara crassifolia, has been achieved efficiently starting from chiral 2,3-O-isopropylidene-d-glyceraldehyde (3) followed by asymmetric allylation and ring-closing metathesis. The antiproliferative activities of compounds 1a, 1b and the unusual bicyclic compound 2 were evaluated against three-cancer cell lines, THP-1 and U-937 (leukemia) and A-375 (melanoma).     

Stereoselective synthesis of aminocyclitol moieties of trehazolin and trehalostatin via enyne metathesis protocol

Stereoselective and efficient synthesis of respective aminocyclitol moieties 1a and 2a of trehazolin and trehalostatin as hexaacetates 1b and 2b using ring-closing enyne metathesis as the key reaction is described.     

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.     

Synthesis of new bicyclic lactam peptidomimetics by ring-closing metathesis reactions

An efficient and versatile synthetic method for the preparation of new fused bicyclic lactams 3a and 3b is described. The spirane cyclopentane nucleus was easily installed by diallylation of the pyroglutamate derivative 18 followed by ring-closing metathesis (RCM). A more practical and stereoselective method for the allylation of the α-methoxy carbamate 21, involving the use of InCl₃ as a Lewis acid, was developed. In the crucial coupling reaction of the diastereomeric mixture of cis- and trans-pirrolidine derivatives 5a and 5b with N-Cbz vinyl phenylalanine only the cis isomer was found to react. An RCM reaction on the dipeptides 25a and 25b followed by catalytic hydrogenation, gave the final epimeric bicyclic lactams 3a and 3b. The same synthetic sequence on the model compound 7, lacking the spiro cyclopentane nucleus, is also reported.     

Total synthesis of (+)-epiepoformin, (+)-epiepoxydon and (+)-bromoxone employing a useful chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate

Enantioselective total synthesis of (+)-epiepoformin 1, (+)-epiepoxydon 2 and (+)-bromoxone 3 using a chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25, it accomplished a formal synthesis of (−)-theobroxide 19, (−)-phyllostine 22, (+)-herveynone 27 and (−)-asperpentyn 28. The usefulness of 6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated.     

A concise synthesis of (±) and a total synthesis of (+)-epiquinamide

A total synthesis of the quinolizidine alkaloid (+)-epiquinamide 1 has been achieved starting from (−)-pipecolinic acid 3. The key step is the highly diastereoselective addition of a TBDMS-protected propargyl alcohol to a chiral aldehyde derived from 3 to give erythro alkynol 19, which is then easily transformed into the desired bicyclic skeleton.     

Total synthesis of 1-deoxy-7,8a-di-epi-castanospermine and formal synthesis of pumiliotoxin-251D

A concise and efficient synthesis of (6R,7S,8R,8aS)-6,7,8-trihydroxyindolizidine (1-deoxy-7,8a-di-epi-castanospermine) 2 is described. The synthesis employs cross metathesis in building the key intermediate 9 and is used effectively in constructing indolizidine skeleton for the total synthesis of 1-deoxy-7,8a-di-epi-castanospermine and also for the bicyclic framework of pumiliotoxin 251D 12, 13. The indolizidine skeleton is achieved in one pot sequence of transformations such as deprotection of Cbz group, reduction of double bond, and cyclization. The configurational and conformational structures of compound 10 are unambiguously confirmed by X-ray analysis.     

New A-ring analogs of the hormone 1α,25-dihydroxyvitamin D3: (2′-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D3

Conceptually new, enantiomerically pure bicyclic tetrahydrofuro[1,2-a]-A-ring phosphine oxides (+)-4 and (−)-4 were successfully prepared from methyl 2-pyrone-3-carboxylate and (S)- or (R)-2-(tert-butyldimethylsilyloxy)methyl-2,3-dihydrofuran, respectively. In addition, (2′-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D₃3a and 3b as new A-ring-modified analogs of the natural hormone 1α,25-dihydroxyvitamin D₃ were readily synthesized by using Lythgoe-type coupling of the A-ring phosphine oxides (+)-4 and (−)-4 with C,D-ring ketone (+)-5.     

Stereoselective total syntheses of (+)-exo- and (−)-exo-brevicomins, (+)-endo- and (−)-endo-brevicomins, (+)- and (−)-cardiobutanolides, (+)-goniofufurone

Stereoselective total syntheses of aggregation pheromones (+)-exo-brevicomin (9a), (−)-exo-brevicomin (9b), (+)-endo-brevicomin (9c), (−)-endo-brevicomin (9d) and styryllactones (+)-cardiobutanolide (14a), (−)-cardiobutanolide (14b), and (+)-goniofufurone (19a) were achieved in good yields from enantiomerically pure highly functionalized furanoid glycal building blocks (1a-d) involving similar synthetic strategies, thus making these furanoid glycals highly useful building blocks in diversity-oriented synthesis (DOS).     

Asymmetric synthesis of 1-deoxynojirimycin and its congeners from a common chiral building block

A new, promising chiral building block 9 for the synthesis of 1-deoxy-4,5-trans-oriented azasugars such as 1-deoxynojirimycin (1) was prepared in only four steps from the Garner aldehyde 10 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring. In practical test, the first synthesis of all four isomers (1 and 6-8) of trans-4,5-orientated 1-deoxyiminosugars using 9 as a common chiral building block was demonstrated.     

Enantioselective synthesis of indolizidine and quinolizidine derivatives from chiral non-racemic bicyclic lactams

Chiral non-racemic bicyclic lactams 2b,c, derived from (R)- and (S)-phenylglycinol, were used in the enantioselective synthesis of (−)-lupinine and 5-epitashiromine, respectively. The efficiency of the synthesis relied on the high diastereoselectivities of formation and reduction of compounds 2b,c.     

Synthesis of l-cyclopentenyl nucleosides using ring-closing metathesis and palladium-mediated allylic alkylation methodologies

The enantiomeric synthesis of l-cyclopentenyl nucleosides is described. The key intermediate (+)-cyclopentenyl alcohol (8) was prepared from methyl-α-d-galactopyranoside 1 using a ring closing metathesis reaction. Transformation of the allylic alcohol 8 into the allylic acetate (9) or carbonate (10), allows their coupling with purine and pyrimidine bases under Pd(0)-catalyzed Tsuji-Trost allylic alkylation's to yield 12a-c. The Pd catalyzed reaction was found to require the use of AlEt₃.     

A stereoselective total synthesis of (+)-α-herbertenol

A stereoselective total synthesis of (+)-α-herbertenol starting from the allyl alcohol 12, readily available in three steps from the monoterpene (R)-limonene, is described. Claisen rearrangement of the aryl allyl ether 10 and concomitant cyclisation furnished a 5:3 mixture of the tricyclic compounds 13 and 14. Degradation of the isopropenyl group followed by cleavage of the central ring and functional group manipulation transformed 13 into (+)-α-herbertenol (1b).     

A facile synthesis of (6S,1′S)-(+)-hernandulcin and (6S,1′R)-(+)-epihernandulcin

A facile total synthesis of (+)-hernandulcin (1) was accomplished from (−)-isopulegol in 6 steps with 15% overall yield. Epoxidation of (−)-isopulegol with m-chloroperbenzoic acid followed by opening of the epoxide 3a with prenyl Grignard afforded the tertiary alcohol 4a with correct C-6 and C-1′ stereochemistry as a major product. Oxidation of the secondary alcohol in compound 4a to the ketone 5a was accomplished in high yield by using TPAP and N-methylmorpholine N-oxide. Conversion of the ketone 5a to α,β-unsaturated ketone via organoselenium intermediate gave (+)-hernandulcin (1). This method was also successfully applied to the synthesis of (+)-epihernandulcin (2).     

Synthetic study of hetisine-type aconite alkaloids. Part 3: Total synthesis of (±)-nominine

Completion of the total synthesis of (±)-nominine (1) is described in detail. Based on the results of the preceding two papers, total synthesis of (±)-nominine was accomplished diverging from the intermediate 7. Thus, following pyrrolidine ring formation through transformation from 7 to 8, the C-ring was constructed by radical cyclization to form 10 from the enyne precursor 9. Subsequent elaboration of the C-ring, followed by formation of the azabicyclic ring system, completed a total synthesis of (±)-1. Single-crystal X-ray analysis of (±)-1 unambiguously confirmed its molecular structure and racemic crystal structure.     

Radical cyclizations of acylsilanes in the synthesis of (+)-swainsonine and formal synthesis of (−)-epiquinamide

Radical cyclization of acylsilane is an useful synthetic methodology. To demonstrate the versatility of this method using the cyclization as a key step, polyhydroxylated indolizidine (+)-swainsonine was synthesized through two different bond connection approaches to construct the bicyclic skeleton. In the first approach, we used 2,3-isopropylidene-d-ribono-1,4-lactone (20) as a chiral building block to form the indolizidine skeleton through a 1,6-cyclization. In the second approach, (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid (23) was used to construct the same ring system through a 1,5-cyclization. Starting from acid 23, we also synthesized exo-1-hydroxyquinolizidin-4-one (56), which was a synthetic intermediate in the synthesis of polyhydroxylated quinolizidine (−)-epiquinamide.     

Asymmetric synthesis of the 6-cyanoindole derivatives as non-steroidal glucocorticoid receptor modulators using (+)- and (−)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate

We have successfully synthesized enantiomerically pure (+)- and (−)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate (+)-1 and (−)-1, which are key intermediates of non-steroidal glucocorticoid receptor modulators, by employing a cinchona alkaloid catalyzed addition of 6-cyanoindole to ethyl trifluoropyruvate. The optimized method can be applied to large-scale synthesis. Furthermore, using the key intermediates (+)-1 and (−)-1, enantiomerically pure glucocorticoid receptor modulators (+)-3 and (−)-3 can be synthesized (>99% ee for both compounds). The glucocorticoid receptor binding affinity was influenced by the stereogenic center at the trifluoromethyl alcohol moiety; compound (−)-3 showed a higher binding affinity compared to (+)-3.