Full and partial differentiation of tris-1,1,1-(hydroxymethyl)ethane via direct and indirect methodology

Tris-1,1,1-(hydroxymethyl)ethane 1 was converted to a series of mono- and disubstituted derivatives. An indirect protocol for the differentiation of the alcohol groups was employed for the synthesis of partially and fully differentiated 1 containing a protected aldehyde unit. Complete differentiation of the alcohol groups was also achieved using a direct strategy (two steps from 1). The first synthesis of 1,3-dialdehydes derived from 1 is reported in two steps.     

A chemoenzymatic total synthesis of ent-narciclasine

The synthesis of the title compound [(−)-1] has been achieved, for the first time, by reacting the aryl boronic acid ester 4 with the aminoconduritol derivative 6 under Suzuki-Miyaura cross-coupling conditions then subjecting the product phenanthridinone 23 to a global deprotection process using trimethylsilyl bromide. The aromatic building block 4 was prepared in ten steps from piperonal while compound 6 was obtained in nine steps from the enantiomerically pure cis-1,2-dihydrocatechol 7. This last compound is available, in multi-gram quantities, through a whole-cell-mediated biotransformation of bromobenzene using genetically engineered organisms that over-express the responsible enzyme, namely toluene dioxygenase. Since the enantiomer of compound 7 is available by related means, the present work also represents a formal total synthesis of the alkaloid narciclasine [(+)-1]. The single-crystal X-ray analysis of compound 13 is reported.     

General entries to C-aryl glycosides. Formal synthesis of galtamycinone

Utilizing a general entry we had developed for the synthesis of C-aryl glycosides, we have prepared the juglone derivatives 18-20 as well as the juglone precursor 13. Because 19 had been previously converted in two steps by Suzuki into galtamycinone (1), its preparation constitutes a total synthesis of 1.     

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.     

Alkaloids from alkaloids: total synthesis of (±)-7a-epi-hyacinthacine A1 from Z-protected tropenone via Baeyer-Villiger oxidation

Baeyer-Villiger oxidations of several tropane derivatives have been investigated. Whereas tropenones 15a-c underwent exclusive epoxidation to 21a-c, the corresponding 6-oxotropane derivative 28 yielded the desired lactone 29. Baeyer-Villiger oxidation was also possible for the O-isopropylidene-protected diols 32a,b. The resulting lactones 33a,b were employed in the total synthesis of (±)-7a-epi-hyacinthacine A₁ (7a-epi-7) via an intramolecular nucleophilic alkyllithium addition to a carbamate as the key lactamization step. The target compound was prepared from tropenone 15b in 10 steps and 14% overall yield. Enzymatic resolution of pyrrolidine (±)-36 provided a formal total synthesis to both enantiomers of 7.     

Laboratory and practical synthesis of Suvorexant,a selective dual orexin receptor antagonist

The development of a laboratory and practical synthesis of Suvorexant 1, using intramolecular Mitsunobu cyclization reaction of intermediate 5 as the key reaction, has been reported. Compound 5 was obtained from known chiral ester 2 in three steps, and the key cyclization proceeded smoothly to provide the core seven-membered ring compound 6, which was transformed into 1 by an additional four-step sequence. The procedure described here needs no chiral-HPLC separation, no classical resolution, and no unique enzyme reactions, and offers an alternative practical synthesis of 1.     

An efficient total synthesis of 9-methoxycarbazole-3-carbaldehyde based on a novel methodology for the preparation of methoxyindoles

A direct synthesis of naturally occurring 9-methoxycarbazole-3-carbaldehyde 1, based on our methodology for the synthesis of 1-methoxyindoles, is reported. A novel benzannulation strategy was employed using ring closing metathesis as the key step in this total synthesis. The synthesis of the natural product 1 has been achieved in seven steps in 14% overall yield from commercial materials and in only four steps from a methoxyindole compound obtained using the new methodology.     

Studies toward the total synthesis of (+)-gelsemine and synthesis of spirocyclopentaneoxindole through intramolecular Michael cyclization

During the approach to the total synthesis of (+)-gelsemine, two novel spirocyclopentaneoxindole compounds 2 and 3 were obtained. Starting from compound 9, spirocyclopentaneoxindole 3 was efficiently and unexpectedly obtained through a Boc migration-intramolecular Michael cyclization cascade procedure. This intramolecular Michael addition strategy allows conveniently access to complex spirooxindole and spirocyclopentaneoxindole derivatives.     

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.     

Synthesis of symmetrical amino and aminomethyl derivatives of Tröger's base via Pd-catalyzed C-C and C-N bond formation

In this paper, we report the synthesis of amino and aminomethyl derivatives of Tröger's base (±)-1 and (±)-2. The key steps in the synthesis of (±)-1 and (±)-2 are Pd-catalyzed amination and cyanation, respectively, of the easily accessible dihalo derivatives (±)-3. These compounds are important intermediates in the synthesis of new ligands and building blocks for H-bonded supramolecular architectures.     

Practical and efficient synthesis of N-fused tricyclic indoles

A practical and efficient synthesis of methyl 6,7,8,9-tetrahydropyrido[1,2-a]indol-10-ylacetate derivatives 6 is reported. This synthetic approach featured the nucleophilic aromatic substitution of 2-piperidinemethanol derivatives 2 with aryl fluorides 1, and the intramolecular Heck coupling as key steps to afford the desired N-fused tricyclic indoles 6.     

A convenient enantioselective synthesis of 3-asymmetrically substituted oxindoles as progesterone receptor antagonists

A convenient enantioselective synthesis of 3-asymmetrically substituted oxindoles is reported. Compound (2) prepared by radical cyclisation of (1) was used for the synthesis of racemic and enantiomerically pure 3-asymmetrically substituted oxindoles. Desulfurisation of (2) using Raney Ni yielded the racemate (5). Addition of (S)-1-phenylethanol to compound (2) yielded the diastereoisomer (21) the structure of which was determined using X-ray crystallography. Using a sequence of steps (21) was converted to the enantiomer (8). The enantiomer (9) was similarly prepared from (2) using (R)-1-phenylethanol.     

Solid-phase synthesis of quinoxaline derivatives using 6-amino-2,3-dichloroquinoxaline loaded on AMEBA resin

The solid-phase synthesis of quinoxaline derivatives 1 was accomplished through successive introduction of building blocks such as amines, methoxide, acid chlorides, and isocyanates into 6-amino-2,3-dichloroquinoxaline 2 loaded on AMEBA resin 3. The method made it possible to obtain the compound 1 in 63-100% purities and 36-89% isolated yields.     

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).     

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.     

A synthesis of 17-epi-calcidiol

The first synthetic approach to 17-epi-calcidiol 4 and congeners is presented. Key steps of the synthesis involve Pd-catalyzed reaction of the androst-16-ene derivative 6 with alkyl diazoacetates producing the respective cyclopropane derivatives 5, and lithium in liquid ammonia reduction of 5 leading to 17α-pregnane-20-carboxylic acid derivatives 9. The side chain was attached to ester 19 in a known manner.     

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring: first asymmetric synthesis of anesthetic (S)-ketamine with high selectivity

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring was performed with respect to the asymmetric synthesis of anesthetic (S)-ketamine 1. Diastereoselective nucleophilic 1,2-addition reaction of phenyllithium to α-ketoxime-ether acetal 9 bearing chiral auxiliary on the α-carbonyl function gave benzyloxyamine 11 major in 83% yield with 82% de, which was converted to the corresponding amino ketone 12. However, the reaction of 2-chlorophenyllithium did not work in which this route was unavailable for the synthesis of 1. Then, an alternative strategy directed toward 1, starting with a compound having 2-chlorophenyl groups in advance, was designed in which the chiral quaternary carbon center bearing a nitrogen atom in the ring is created by the enantioselective reduction of the atropisomeric intermediate ketone 18, and the sequential allyl cyanate-to-isocyanate rearrangement with complete 1,3-chirality transfer. The first asymmetric synthesis of 1 with excellent selectivity (>99% ee) was accomplished by a short path according to the strategy.     

An alternative approach toward 2-aryl-2H-pyrazolo[4,3-c]-quinolin-3-ones by a multistep synthesis

A series of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones derivatives 6 and 7 was conveniently prepared. A multistep synthesis was carried out starting from dichloro- and bromoanilines (1a-b) and diethyl 2-(ethoxymethylene)malonate using a slightly modified Gould-Jacobs reaction. In this work we present a novel chlorination strategy to prepare quinoline derivatives 4 in excellent yields as key intermediates in the synthesis of the target compounds. Several reaction conditions were evaluated to optimize the formation of pyrazoloquinolinone nucleus. Differences in chemical behavior of both chloroquinolinones 4a-b with aryl and benzyl-hydrazines are also discussed.     

Preparation of 3-hydroxyoxindoles with dimethyldioxirane and their use for the synthesis of natural products

This work describes a general protocol for the oxidation of indole and oxindole derivatives with dimethyldioxirane to give 3-hydroxyoxindoles present in many natural products. This strategy allowed us to synthesize the natural product 1, to carry out the first total synthesis of 4, a formal total synthesis of donaxaridine (5) and to achieve the synthesis of pyrroloindoline 8, a debromo analogue of the natural product flustraminol B (7).     

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).