The first total synthesis of telephiose A

The first total synthesis of telephiose A (1), a novel trisaccharide ester having two acetyl groups and two benzoyl groups, was achieved by using glucosyl donor 6 and disaccharide acceptor 12. The crucial key step was the stereoselective construction of the β-d-glucosidic linkage featuring the neighboring group participation of the 2-O-N-phenylcarbamoyl group (of donor 6), which can be selectively deprotected in the presence of acetyl and benzoyl groups. Donor 6 was prepared from d-glucose in eight steps (33% yield), whereas acceptor 12 was prepared from sucrose in six steps (35% yield). Precursors 6 and 12 were reacted in subsequent reactions (five steps) to afford 1 in 22% yield.     

Synthetic studies on reidispongiolide A, an actin-depolymerizing marine macrolide: synthesis of C11-C22 and C23-C35 segments

The C11-C22 and C23-C35 segments 2 and 3 of reidispongiolide A (1), an actin-depolymerizing marine macrolide, were synthesized enantioselectively in 12 steps from (R)-glycidyl trityl ether and in 12 steps from chiral ketone 15, respectively.     

Synthesis and reactions of two stereoisomeric [4.5.5.5]fenestranes with bridgehead substituents

The [4.5.5.5]fenestranes 2 and 3 with two different functionalities were prepared in seven steps with overall yields of 5% and 10%, respectively. For introduction of a bridgehead double bond the removal of the tertiary hydroxy group was investigated in the two stereoisomeric hydroxyketones 12 and 15. Whereas the dehydration readily occurred in 12, a ring opening reaction was observed for 15.     

Enantioselective allyltitanations: synthesis of the proposed structures for passifloricin A

The stereoselective total synthesis of the proposed structures P1 and P2 for passifloricin A was achieved in 12 steps from n-hexadecanal by using enantioselective allyltitanations and a ring closing metathesis reaction as the key steps. Both P1 and P2 are different from passifloricin A.     

First synthesis of nitro-substituted 2,2-diphenyl-2H-1-benzopyrans via the ipso-nitration reaction

The first synthesis of a series of nitro-substituted 2,2-diphenyl-2H-1-benzopyrans is reported. Our synthetic approach is based on a linear synthesis in two steps from appropriate brominated 2,2-diphenyl-2H-1-benzopyrans 12-17, which requires the preliminary preparation of bromophenols 7-11. These latter were easily obtained by the reaction of phenols 1-5 with a mild and selective brominating agent tetrabutylammonium tribromide (TBA·Br₃). The key intermediates 12-17 were efficiently elaborated through an univocal classic chromenization between the commercially available 1,1-diphenyl-2-yn-1-ol and the brominated phenols 6-11. The compounds 12-17 so obtained were converted into arylboronic acids 18-23 by a metalation/boronylation sequence, followed by acid hydrolysis. From advanced building blocks 18-23, the introduction of nitro group, which constitutes the ultimate step of our strategy, was achieved by an ipso-nitration reaction using the Crivello's reagent. This highly selective method provides only the ipso-nitrated products 24-29 in moderate to high yield.     

An expedient synthesis of 7(S)-ethyl-8(R or S)-indolizidinols based on a thiophene reductive desulfurization

Chiral hexahydrothieno[2,3-f]indolizine-4,7-dione (S)-12 and the ancillary alcohol 13 were generated from thiophene-2-carboxaldehyde and (S)-glutamic acid in three and four steps, respectively, in good overall yields and both high enantio- and diastereomeric purities. Applying a thiophene reductive desulfurization, compound 12 was readily converted into 7(S)-ethyl-8(S)-indolizidinol 9. The 8(R)-epimer of 9 was advantageously obtained using the Mitsunobu alcohol inversion or, starting from 13, by chemical separation after O-benzylation and lactam reduction. During these studies, the reduction of regioisomers of 12 and 13, namely 17 and 18, was investigated and the results obtained are also discussed.     

Total synthesis of (+)-ambruticin S

A convergent total synthesis of the novel antifungal agent ambruticin S (1) has been completed from the assembly of intermediates 18, 33 and 52 that served as the respective A-, B-, and C-ring precursors. The first generation approach to a potential A-ring intermediate eventuated in the synthesis of 9a via a route that featured oxidation of the dihydroxy furan 2 and elaboration of the dihydropyranone 3 derived therefrom. Although 9a served as a precursor of 31E to complete a formal synthesis of 1, there were several inefficiencies associated with the preparation of 9a. A more expedient and efficient route to an A-ring subunit was devised that commenced with the carbohydrate-derived bisacetonide aldehyde 10 and produced 18 in five steps and 46% overall yield. The synthesis of the cyclopropyl sulfone 33 was initiated with the enantioselective cyclopropanation of 19 catalyzed by Rh₂[5(S)-MEPY]₄. Ring opening of the resultant lactone 20 followed by a series of refunctionalizations gave 33 in a total of seven steps and 46% yield from 19. Coupling of the A- and B-ring precursors 18 and 33 was then achieved via a modified Julia coupling followed by deprotection and oxidation to furnish the key intermediate 35. The dihydropyran core of the C-ring subunit precursor 49 was formed from the ring closing metathesis of the diene 48, which was prepared in three steps from the known epoxide 45, followed by oxidation. A chelation-controlled addition to the methyl ketone 49 set the stage for a stereoselective [2,3]-Wittig rearrangement that delivered the alcohol 51 that was then transformed in two steps to the sulfone 52. A traditional Julia coupling of 52 and 35 proceeded with excellent stereoselectivity, and subsequent removal of the various protecting groups gave ambruticin S (1). The longest linear sequence was 13 steps and proceeded in 4.3% overall yield.     

Improved synthesis of 1,4-dideoxy-1,4-imino-d-galactitol, an inhibitor of E. coli K12 UDP-Gal mutase and mycobacterial galactan biosynthesis

The E. Coli K12 UDP-Gal mutase inhibitor 1 was prepared from d-glucose in 5 steps (42% overall yield). The 4-azido galactose derivative 11, leading to 1, was formed by treatment of galactose dithioacetal 7 with mercuric oxide and mercuric chloride in acetone. To obtain 7, acetal 3 was tosylated or triflated and treated with NaN₃.     

Synthesis of 2′-β-C-methyl-neplanocin derivatives as anti-HCV agents

The synthesis of 2′-β-C-methyl-neplanocin derivatives is described. The key intermediate cyclopentenyl alcohol 12 is prepared from sugar 5 in 12 steps. Coupling of 12 with appropriately protected purine, 7-deaza pyrimidine, uracil and pyrimidine bases via the Mitsunobu reaction followed by deprotection afforded the target cyclopentenyl nucleosides (18-23, 27). The synthesized compounds were evaluated as potential inhibitors of the hepatitis C virus (HCV) in vitro. Unfortunately, none of them show anti-HCV activity below EC₅₀ 100 μM.     

Enantioselective synthesis of (+)-anatoxin-a via enyne metathesis

A concise synthesis of the potent nAChR agonist (+)-anatoxin-a (1) has been completed by a series of nine chemical operations and in 27% overall yield from commercially available d-methyl pyroglutamate (12). The strategy featured the application of a new protocol for the diastereoselective synthesis of cis-2,5-disubstituted pyrrolidines bearing unsaturated side chains and an intramolecular enyne metathesis to provide the bridged bicyclic framework of 1. Thus, d-methyl pyroglutamate (12) was converted in five steps to 32, which underwent facile enyne metathesis to deliver the bicyclic diene 33. Selective oxidative cleavage of the less substituted carbon-carbon double bond in 33 followed by deprotection furnished (+)-anatoxin-a (1).     

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).     

An efficient synthesis of dienic nucleoside analogues via a Mitsunobu reaction

Nucleoside analogues 9 and 12 were obtained in good yields from alcohol 7 which, under Mitsunobu conditions, led to the title products after deprotection steps.     

Efficient synthesis of analogs of safflower yellow B, carthamin, and its precursor: two yellow and one red dimeric pigments in safflower petals

The synthesis of analogs (8, 12, 14) of two yellow pigments, safflower yellow B and the precursor of carthamin, and carthamin itself, a red pigment, which are produced in safflower (Carthamus tinctrious L.) petals and, which have a common dimeric quinochalcone structure, is reported. The key compound for the synthesis of these analogs, (p-hydroxycinnamoyl)filicinic acid (7) was synthesized in six steps from phloroglucinol in a total yield of 39%, which was reacted with 2,3,4,5,6-penta-O-acetyl-aldehydo-d-glucose, glyoxylic acid, and ethyl orthoformate in the presence of base to afford the corresponding analog, 8, 12, 14, in good yields, respectively. Precursor analog 12 was then converted to carthamin analog 14 by oxidative decarboxylation by treatment with potassium permanganate as well as the natural specimen.     

Synthesis of a metabolite of an anti-angiogenic lead candidate based on a d-glucosamine motif

A rapid synthetic access to ACL 21269 was established in 12 steps starting from thiogylcoside 9 utilizing synthons 8 and 6 to introduce the pharmacophores at positions 1 and 2. The functional groups decorating the glucosamine scaffold were introduced in a particular order and common protecting groups were employed to establish a robust synthetic process.     

Synthesis and characterization of coumarin and dimedone-derived diazabicycles

A series of diazabicyclic derivatives were prepared in three to four steps from p-anisidine and p-nitrobenzaldehyde. The key step of the synthesis involved the acid-catalyzed coupling of 4-aminocoumarin or dimedone derivatives with amino alcohols 3 or 7 to give the ring-opened forms 4, 10, 12 and the ring-closed diazabicycles 5, 6, 9, 11. When 4-alkylaminocoumarins were used as the coupling reagents, the major cyclized product was N-dealkylated diazabicycle 5, rather than the corresponding N-alkylated products. Alternatively, compound 4 was cyclized by DDQ oxidation to produce quinone imine 13. The molecular structures of the synthesized compounds were characterized by X-ray crystallography.     

Stereoselective synthesis of a fully protected C13-C23 fragment of tedanolide

The combination of a high-yielding dienyllithium addition and a highly diastereoselective 1,2-reduction allows the preparation of the completely protected C₁₃-C₂₃ fragment 3 of the potent cytotoxic agent tedanolide 1. A convergent approach was used, namely a late stage coupling of the dienyllithium 16 with the selectively protected aldehyde 5 followed by oxidation-reduction and final epoxidation to give 3. The dienylstannane 4 was prepared from the dibromide 6 in five steps, the key step being the highly regio- and stereoselective stannylcupration of the alkyne 7. The commercially available hydroxy ester 10 was converted in 11 steps to the aldehyde 5. The compound 3 could potentially be a key intermediate for the synthesis of tedanolide 1.     

Asymmetric synthesis of (+)-1-deoxynojirimycin and (+)-castanospermine

Asymmetric total syntheses of (+)-1-deoxynojirimycin (1) and (+)-castanospermine (2) are described. Starting from diene 3, the required absolute stereochemistry is introduced by an asymmetric hydroxylation followed by epoxidation. An intramolecular cyclization of amine 17 gives access to the corresponding tetrasubstituted piperidine 18, which is a precursor to compounds 1 and 2. (+)-Deoxynojirimicyn (1) was obtained in 36% yield over 11 steps from diene 3, while (+)-castanospermine (2) was achieved in 13% after 19 steps from the same starting material.     

Synthesis of Methylenecyclopropane Analogues of Antiviral Nucleoside Phosphonates

Synthesis of methylenecyclopropane analogues of nucleoside phosphonates 6a, 6b, 7a and 7b is described. Cyclopropyl phosphonate 8 was transformed in four steps to methylenecyclopropane phosphonate 16. The latter intermediate was converted in seven steps to the key Z- and E-methylenecyclopropane alcohols 23 and 24 separated by chromatography. Selenoxide eliminations (15→16 and 22→23+24) were instrumental in the synthesis. The Z- and E-isomers 23 and 24 were transformed to bromides 25a and 25b, which were used for alkylation of adenine and 2-amino-6-chloropurine to give intermediates 26a, 26b, 26c and 26d. Acid hydrolysis provided the adenine and guanine analogues 6a, 6b, 7a and 7b. Phosphonates 6b and 7b are potent inhibitors of replication of Epstein-Barr virus (EBV).     

Towards stable di-carba analogues of guanofosfocins

Guanofosfocins are strong inhibitors of chitin synthases, but also very prone to hydrolytic cleavage. Two advanced intermediates 15 and 20 for the synthesis of stable di-carba-guanofosfocins were prepared via ester 11. Acylation of the allylic C-glycoside 6 with riburonic acid chloride 10 afforded ester 11 in 79% yield. This ester was converted to 15 in four steps and in 54% yield and to 20 in eight steps and in 20% yield.