Enantioconvergent synthesis of (-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine,an intermediate to delta-opioid receptor ligands

A convenient, high-yield enantioconvergent synthesis of (-)-1-allyl-(2S,5R)-dimethylpiperazine from trans-2,5-dimethylpiperazine has been developed. This compound is an important intermediate in the synthesis of delta-opioid receptor ligands. The process allows for the laboratory preparation of 100 g quantities of this enantiomerically pure diamine without chromatography. The key steps in the sequence were an efficient optical resolution using relatively inexpensive resolving agents, followed by interconversion of the unwanted (+)-enantiomer into the desired (-)-enantiomer.     

Total synthesis of (+)-dihydrocuscohygrine and cuscohygrine

The first enantioselective synthesis of (+)-dihydrocuscohygrine 1 and cuscohygrine 2 is presented. 1 was obtained in nine steps and 30% overall yield with a ruthenium-catalyzed tandem ring rearrangement metathesis key step starting from enantiomerically pure cycloheptene-1,3,5-triol derivative 6. The unknown absolute configuration of natural dihydrocuscohygrine 1 could be determined as (S,S)-(-). Cuscohygrine 2 was obtained by Jones oxidation of 1 in quantitative yield but unfortunately with complete epimerization.     

Enantioselective syntheses of carbanucleosides from the Pauson-Khand adduct of trimethylsilylacetylene and norbornadiene

A new enantioselective approach to carbanucleosides from Pauson-Khand (PK) adduct 1 is disclosed. The chiral cyclopentenone 1 is readily accessible in enantiomerically pure form via PK reaction of trimethylsilylacetylene and norbornadiene using N-benzyl-N-diphenylphosphino-tert-butyl-sulfinamide as a chiral P,S ligand. (-)-Carbavir and (-)-Abacavir were enantioselectively synthesized starting from (-)-1. The key steps of the sequence are a photochemical conjugate addition of a hydroxymethyl radical, a retro-Diels-Alder reaction, and a palladium catalyzed allylic substitution to introduce the nucleobase.     

A concise route to a key intermediate in the total syntheses of (+)-tirandamycic acid and (-)-tirandamycin a 2

An efficacious, asymmetric synthesis of the 2,9-dioxabicyclo[3,3,1]nonane 4 has been completed in nine chemical steps from 4,5-dimethylfuraldehyde (8). Since enantiomerically pure 4 has been previously converted in five steps by Ireland into (+)-tirandamycic acid (3) and more recently by Schlessinger into (-)-tirandamycin A (1), this achievement constitutes in a strictly formal sense the total syntheses of these substances. The key step in the synthesis of 4 features the transformation of the enantiomerically pure furfuryl diol 25 into 29 by initial selective oxidation of (the furan ring and subsequent acid-catalyzed bicycloketalization.     

SmI2-mediated cross-coupling of nitrones with β-silyl acrylates: synthesis of (+)-australine

The SmI(2)-mediated cross-coupling of nitrones with β-silyl-α,β-unsaturated esters, followed by zinc reduction, allows an efficient and highly diastereoselective preparation of β-silyl lactams, which are precursors of β-hydroxy lactams through Tamao-Fleming oxidation. By applying the method to a cyclic, carbohydrate-derived nitrone, a new synthesis of (+)-australine has been realized in only 11 steps and in 21% overall yield from L-xylose.     

The total synthesis of (−)-connatusin A, a hirsutane-type sesquiterpene isolated from the fungus Lentinus connatus BCC8996

The title sesquiterpenoid natural product 1 has been prepared for the first time using the enantiomerically pure cis-1,2-dihydrocatechol 3 as starting material. Key steps associated with the synthesis include a Diels-Alder cycloaddition reaction of the acetonide 5 with cyclopentenone (4) and an oxa-di-π-methane rearrangement of bicylco[2.2.2]octenone 6 derived from the initial adduct. The product of this sequence, the cyclopropannulated triquinane 7, was elaborated, over a further eight steps including those involving Upjohn dihydroxylation and Swern oxidation protocols, to the target 1. A single-crystal X-ray analysis served to confirm the structure of this synthetically derived material.     

An Efficient Total Synthesis of Carbocyclic 2′-Deoxyribonucleosides

The present work describes a new and efficient method for the preparation of either racemic or enantiomerically pure carbocyclic 2′-deoxyribonucleosides 1 . Key steps are the efficient assembly of the racemic carbocyclic 2′-deoxyribose core (±)- 12 , its enzymatic resolution, and a new approach to covalently link the purine and pyrimidine bases with the cyclopentane moiety via the cyclic sulfate (+)- 19 . This total synthesis of enantiomerically pure and racemic carbocyclic 2′-deoxyribonucleosides 1 represents one of the most efficient approaches reported to date. Starting from cyclopentadiene, the four carbocycles corresponding to the naturally occurring 2′-deoxyribonucleosides could be prepared in 12 steps and 9–12% overall yield. For the corresponding racemic compounds, 10 steps were used with overall yields between 22 and 30%.     

Improved synthesis of structural analogues of (−)-epicatechin gallate for modulation of staphylococcal β-lactam resistance

The high-yielding synthesis of enantiomerically pure epicatechin gallate analogues where the A and/or B-ring hydroxylation is reduced or altered has been achieved by optimising routes to the catechin stereochemistry. The B-ring analogues were synthesised by using an electrophilic ring closure onto an enantiomerically enriched epoxide as a key step. The A and B-ring hydroxyl-deleted analogues were synthesised through a Mitsunobu cyclisation. For the B-ring analogues, the anti- (catechin) stereochemistry was converted to the syn- (epicatechin) stereochemistry by a known oxidation/reduction protocol. Absolute stereochemistry was derived from either a Sharpless epoxidation or asymmetric dihydroxylation.     

Studies towards the synthesis of ertugliflozin from l-Arabinose

A new method for the diastereoselective synthesis of enantiomerically pure ertugliflozin was developed. The crucial step involves an aldol condensation between 1-(4-chloro-3-(4-ethoxybenzyl)phenyl)ethanone and (4R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-dioxolane-4-carbaldehyde, which was prepared from known 2-C-trityloxymethyl-2,3-O-isopropylidene-l-erythrose (easily accessible in three steps from l-arabinose) by standard reduction/oxidation and protection/deprotection manipulations. Dihydroxylation of the aldol condensation product and further global deprotection led to the formation of the target molecule.     

Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids

A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.     

Asymmetric synthesis of rubiginones A(2) and C(2) and their 11-methoxy regioisomers

Convergent enantioselective syntheses of angucyclinone-type natural products rubiginones A(2) (2) and C(2) (1) and their 11-methoxy regioisomers 3 a and 3 b have been achieved by using two domino processes from a common enantiomerically pure 1-vinylcyclohexene 4. Key steps in the synthesis of this diene were the stereoselective conjugate addition of AlMe(3) on (SS)-[(p-tolylsulfinyl)methyl]-p-quinol (9) and the elimination of the beta-hydroxy sulfoxide fragment, after oxidation to sulfone, to recover a carbonyl group. The first domino sequence comprised Diels-Alder reaction with a sulfinyl naphthoquinone followed by sulfoxide elimination. An efficient opposite regioselection in the cycloaddition step was achieved in the convergent construction of the tetracyclic skeleton using a sulfoxide at C-2 or C-3 of the dienophiles 5 or 6, derived from 5-methoxy-1,4-naphthoquinone. The second domino process, triggered by oxygen and sunlight, allowed the transformation of the initial tetracyclic adducts into the final products after B ring aromatization, silyl deprotection and C-1 oxidation.     

Practical enantioselective synthesis of endothelin antagonist S-1255 by dynamic resolution of 4-methoxychromene-3-carboxylic acid intermediate

A practical multikilogram-scale synthesis of enantiomerically pure S-1255 (1), a potent and orally active ET(A) receptor antagonist, is described. Utilizing readily available starting materials and reagents, the entire sequence of reactions starting from 2,5-dihydroxyacetophenone 8 proceeded under mild conditions to give 1 in an excellent chemical yield (8 steps, 41% overall yield) and in a high enantiopurity (98% ee). The crucial step of the synthesis is a dynamic resolution of key intermediate 16. (R)-Methoxy acid (R)-16 having 97-99% ee was obtained in 83-84% yield from racemic 16 as a crystalline (1S,2R)-(+)-norephedrine or (+)-cinchonine salt by the dynamic resolution comprising concurrent crystallization and in situ racemization. A mechanism of the dynamic resolution through a ring-opened zwitterionic intermediate is discussed. In the final synthetic step, an effective carbon-carbon bond formation between the C4 carbon and the p-anisyl group was accomplished by a conjugate addition-elimination reaction of Grignard reagent 3 to (R)-16 to give 1 having 98% ee. Owing to high efficiencies of functional group transformations, carbon-carbon bond formations, and the dynamic resolution, the synthesis required no chromatographic purification and was amenable to a multikilogram-scale preparation. Several kilograms of 1 for clinical trials were successfully prepared by this process.     

A flexible enantioselective synthesis of the isofurans

Recently, the isolation of a new class of human arachidonic acid tetrahydrofuran oxidation products, the isofurans (IsoF's), was reported. These new compounds are available from natural sources only in microgram quantities as mixtures. The enantioselective preparation of a versatile epoxide intermediate and its conversion to the enantiomerically pure isofurans SC-Delta(13)-9-IsoF and 15-epi-SC-Delta(13)-9-IsoF are described. This synthesis will make these metabolites available for physiological evaluation.     

Efficient synthesis of enantiomerically pure trans-2,5-bis(arylethynyl)pyrrolidines. A new entry into C2-symmetric chiral secondary amines

A new class of C₂-symmetric pyrrolidine derivatives bearing arylethynyl groups at the 2,5-positions has been synthesized in enantiomerically pure form from 1,7-octadiyne-3,6-diol in five steps. Some notable features of the synthesis are: (i) the formation of a separable diastereomeric mixture of pyrrolidine carbamates using a newly prepared chiral chloroformate; and (ii) the development of a new method for the deprotection of the carbamate via a novel SmI₂-promoted electron transfer process.     

Practical formal total synthesis of (rac)- and (S)-camptothecin

A practical, efficient and scalable formal total synthesis of (rac)- and (S)-camptothecin is described, which proceeds via the known DE ring building blocks 19 and (S)-19, respectively. The racemic synthesis starts from diethyl oxalate and uses straightforward carbonyl chemistry in order to generate the pyridone ring system. 19 was formed in 8.4% overall yield over 9 linear steps avoiding any chromatographic purification. The asymmetric version of this approach encompassed a diastereoselective Grignard addition to the enantiomerically pure alpha-ketoester 30 in order to generate the (S)-configured quaternary stereocenter. The auxiliary could be recycled in high yield and was successfully reused multiple times. The final steps paralleled the racemic approach. (S)-19 was thus prepared in 9.4% overall yield (er = 95 : 5) over 10 steps.     

A stereoselective synthesis of (+)-L-733,060 from ethyl (R)-(+)-2,3-epoxypropanoate

An asymmetric synthesis of neurokinin substance P receptor antagonist (+)-L-733,060 starting from enantiomerically pure ethyl (R)-(+)-2,3-epoxypropanoate (ethyl glycidate) is described. The synthesis relies on a diastereoselective reductive amination, regioselective intramolecular epoxide opening, and in situ cyclization as the key steps.     

Stereoselective synthesis of (-)-cephalotaxine and C-7 alkylated analogues

A total asymmetric synthesis of (-)-cephalotaxine is reported. The chemistry of alpha,beta-unsaturated gamma-lactams was used to access the 1-azaspiro[4.4]nonane skeleton in enantiomerically pure form via a stereocontrolled semipinacolic rearrangement of an alpha-hydroxyiminium ion. This spiro compound was transformed into (-)-cephalotaxine without any racemization or epimerization by following the racemic synthesis reported by Kuehne. We thus performed a total synthesis of (-)-cephalotaxine in 98.7% ee with an overall yield of 9.8% over a 16 steps sequence. This synthetic process was adaptable to the access of some alkylated analogues.     

A new stereocontrolled entry into the anthracyclinone families. Part 1: Synthesis of bicyclic precursors of 4-demethoxy-7-deoxy-derivatives

A new and versatile strategy to obtain enantiomerically pure bicyclic precursors of compounds belonging to different anthracyclinone families is reported. Completely stereoselective hydrocyanation of (R)-4-(2,5-dimethoxyphenyl)-1-p-tolylsulfinyl-2-butanone and further intramolecular capture of the Pummerer intermediate generated from the resulting sulfinylcyanohydrin are the key steps to obtain the bicyclic nitrile 2 with the proper configuration and functionality at C-9.     

Chiral 1,4-bis-diphosphine ligands from optically active (Z)-olefines

The catalytic asymmetric hydrogenation of prochiral ketones was carried out with Ru(II) complexes prepared from new chiral diphosphine ligands, cis-(R,R)-2,5-bis[(diarylphosphino)]-3-hexenes. These new ligands were prepared from enantiomerically pure (R,R) or (S,S)-(Z)-3-hexene-2,5 diol and enantiomeric excesses up to 85% were obtained in the reduction of 2-benzamidomethyl-3-oxobutanoate, starting material for the synthesis of 4-acetoxy-2-azetidinone.     

Synthesis of (+)-1-epiaustraline

A highly efficient total synthesis of (+)-1-epiaustraline ((+)-1), a tetrahydroxypyrrolizidine alkaloid of the alexine/australine subclass, is described. The key step is a tandem intramolecular [4 + 2]/intermolecular [3 + 2] nitroalkene cycloaddition involving dienylsilyloxy nitroalkene 3 and chiral vinyl ether 4, which establishes four of the five stereocenters present. The final center was installed by a diastereoselective dihydroxylation. Hydrogenolytic unmasking of the nitroso acetal tosylate 17 containing the silyl ether linkage was thwarted by a slow alkylation and an undesired Peterson-type elimination. Prior removal of the silicon moiety by Tamao-Fleming oxidation proceeded in excellent yield and provided a substrate suitable for hydrogenolysis and deprotection. The complete synthesis required only 10 steps to deliver the (+)-1-epiaustraline in 7.0% overall yield.