Novel synthesis of enantiomerically pure natural inositols and their diastereoisomers

The various inositol polyphosphates have been found to trigger many important biological processes. Although the knowledge of this phosphoinositide signaling system has been discovered in the past 10 years, many factors remain unclear. For this reason, there is an increased demand for supplies of D-myo-inositol and particularly of novel analogues to investigate these biological mechanisms in more detail. Herein, we report the efficient syntheses of all diastereoisomers of inositol starting with 6-O-acetyl-5-enopyranosides. Conversion of 6-O-acetyl-5-enopyranosides into the corresponding substituted cyclohexanones (Ferrier-II rearrangement) was found to proceed efficiently with a catalytic amount of palladium dichloride. Stereoselective reduction of beta-hydroxy ketones obtained provided the precursors to all inositol diastereoisomers in good to excellent yields and with high stereoselectivities. Good accessibility of these enantiomerically pure inositol diastereoisomers results in the efficient syntheses of D-myo-inositol 1,4,5-trisphosphate and D-myo-inositol 1,3,4,5-tetrakisphosphate.     

Novel synthesis of chiral,enantiomerically pure thiodiglycols and diglycols

Natural α-hydroxy acids have been converted in a sequence of O-protection, reduction, O-activation, thioether and ether formation and deprotection to chiral, non-racemic β,β′-dihydroxy thioethers 1a, 1b and ether 1c. Overall yields are excellent (75%). In an attempt to synthesize the respective dihydroxy ether 1d derived from mandelic acid 1,3-dioxolane derivatives 7 were obtained.     

Bioconjugates of enantiomerically pure organopalladium compounds by metal-assisted positional selective transesterifications at palladium enolates

The synthesis of enantiomerically pure palladatricyclo[4.1.0.0(2,4)]heptanes and their modification by an unprecedented and very efficient positional selective transesterification is described. The mild reaction conditions are most probably based on an acceleration of the transesterification due to assistance by the metal. This novel approach allows straightforward access to a large number of structurally diverse organometallic complexes. The functional groups on the newly installed ester moieties were modified by using standard peptide synthesis protocols, Sonogashira reactions, and nucleophilic substitution reactions. The cellular uptake of these organometallic species was traced by confocal microscopy and their biological activity was evaluated by using different cell lines. Inhibition of cell growth and induction of apoptotic cell death by these novel palladium heterocycles are equivalent to Cisplatin.     

Diastereo- and enantiomerically pure allylboronates: their synthesis and scope

Allylboronates are highly attractive reagents for allyl additions. Enantiomerically pure, stable reagents with a stereogenic centre in alpha-position to boron are especially versatile, albeit often difficult to synthesize. Starting from boron-containing allyl alcohols 6 and 7, which are discussed in detail herein, a set of reagents were obtained via [3,3]-sigmatropic rearrangements and consecutive transformations in the side chain. The configurations could be established first by chemical correlation, but also by X-ray crystallography (16, 18, 34, and 39). Allyl additions were performed resulting in the formation of predominantly (Z)-configured homoallylic alcohols (31, 43-45) with high enantiomeric excess. Detailed investigations on the matched-mismatched interaction between the reagents 15/16 (and ent-15/ent-16, respectively) and isopropylidene glyceraldehyde 42d are presented.     

Total synthesis of the four enantiomerically pure diastereomers of 8-F(2t)-isoprostane

Syntheses of the four enantiomerically pure diastereomers of 8-F(2t)-isoprostane (5-8) are described. The key to this approach was to prepare the racemic alcohol 9 in high diastereomeric purity and then resolve 9 by lipase-mediated acetylation to yield the enantiomerically pure alcohols 30 and 32.     

Diversity-oriented synthesis of enantiomerically pure steroidal tetracycles employing Stille/Diels-Alder reaction sequences

Various steroid analogues were synthesized by Stille coupling of bicyclo[4.3.0]nonenylstannanes cis-/trans-8 and 14 with cyclohexenol triflates 17 and 18 and subsequent Diels-Alder reactions of the resulting dienes. The enantiomerically pure bicyclo[4.3.0]nonenylstannanes cis- and trans-8 were prepared in good yields via the enol triflates cis- and trans-7, obtained from the bicyclo[4.3.0]non-2-en-3-one 5. The alkenylstannane 14 was obtained from the [2+2] cycloadduct 10 a produced from addition of dichloroketene to the enantiomerically pure and protected bishydroxycyclohexadiene 9 a (65 %). Treatment of 10 a with diazomethane, reduction of the dichloromethylene group, and trapping with tributyltin chloride after lithium-for-bromine exchange, yielded the bicyclo[4.3.0]nonenylstannane 14 (23 % over four steps). Stille couplings provided the tricyclic dienes cis-/trans-19 in good yields (73-77 %), whereas the tricyclic diene 20 was obtained in only 34 % yield at best. Diels-Alder reactions of trans-19 with various reactive dienophiles yielded the novel steroidal compounds trans-21 to trans-26 with complete diastereoselectivity. Heating the dienes cis-19 or 20 with maleic acid derivatives provided the corresponding tetracycles cis-23alpha,beta and 27alpha,beta with a cis-C,D ring junction, each as mixtures of two diastereomers. Less reactive dienophiles required higher temperatures to promote the relevant cycloaddition with trans-19 to furnish several stereoisomeric forms of trans-28 and trans-29 in significantly lower yields (31-45 %). The selected steroid analogues trans-22 and trans-23 were deprotected in two steps by using acid catalysis to provide trans-31 and trans-33 (91 and 80 % over two steps). Cyclopropanation of trans-30 yielded the cyclopropasteroid analogue 34 (74 %), treatment of which with trifluoroacetic acid furnished the cyclopropasteroid 35 and the 2-methyl-substituted steroid analogue 36 in 40 and 12 % yield, respectively. Aromatic B-ring steroids 38 (69 %) and 39 (5 %) were accessed by dehydrogenation of trans-24 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.     

Efficient synthesis of enantiomerically pure dihydropyrans

cis- and trans-2-Substituted-3,6-dihydro-2H-pyran-3-ols have been prepared via an aldol condensation/ring-closing metathesis/enzymatic resolution sequence. The process can be scaled up to yield gram quantities of enantiomerically pure material.     

Efficient syntheses of penta-hydroxylated cyclohexanones via PdCl2-mediated Ferrier-II reaction of 6-O-acetyl-5-enopyranosides

The conversion of 6-O-acetyl-5-enopyranosides into fully oxygenated cyclohexanones was found to proceed efficiently with a catalytic amount of palladium chloride under neutral conditions. This method was proved to be superior in efficacy to the conventional Hg method.     

An access to 3,4-(aminomethano)proline in racemic and enantiomerically pure form

Protected racemic and enantiomerically pure 3,4-(aminomethano)prolines rac-9 and (2S,2'R,3R,4R)-9 have been prepared applying a titanium-mediated reductive cyclopropanation as a key step. Thus, cyclopropanations of N,N-dibenzylformamide with titanacyclopropanes generated in situ from racemic or enantiomerically pure tert-butyl N-Boc-3,4-dehydroprolinates rac-8 or (S)-8 proceed diastereoselectively, and furnish the protected racemic and enantiomerically pure diamino acid 9. The latter was incorporated into three tripeptides containing glycyl, alanyl and phenylalanyl moieties.     

Asymmetric synthesis of enantiomerically pure zingerols by lipase-catalyzed transesterification and efficient synthesis of their analogues

The achiral zingerone 1, readily available from ginger, can be easily transformed into chiral derivatives. Zingerol 2, a reduced product of zingerone 1 is expected to be an important new medicinal lead compound. We have achieved a concise synthesis of optically active zingerol (R)-2 and (S)-2 by the lipase-catalyzed stereoselective transesterification of racemic 2. Under the optimized conditions, a lipase from Alcaligenes sp. (Meito QLM) and vinyl acetate in i-Pr₂O or hexane at 35 °C within 1 h gave the alcohol (S)-2 and the acetate (R)-9 with high enantioselectivity without producing acetylated by-products. Since optically active (S)-2 and (R)-9 were obtained through lipase-catalyzed transesterification, other enantiomerically pure novel compounds could all be synthesized.     

Microwave assisted synthesis of enantiomerically pure allylboronates

Stable allylboronates with a stereogenic centre α to the boronic ester moiety represent versatile reagents for stereoselective synthesis of homoallylic alcohols. Use of microwave irradiation in desilylation and sigmatropic rearrangement reactions allows rapid synthesis of α-chiral allylboronates utilized in the highly diastereo- and enantioselective synthesis of (Z)-configured homoallylic α-hydroxy esters by allyl additions to ethyl glyoxylate.     

A concise synthesis of enantiomerically pure aroyl-l-alanines and dihydroaroyl-l-alanines

Straightforward preparation of enantiomerically highly enriched N-substituted aroylalanines has been developed. This process involves the combination of crystallization-induced asymmetric transformation and a conjugate addition of N-nucleophiles to the corresponding aroylacrylic acids. Further transformations to 3,4-dichlorobenzoylalanine and aroyl-l-alanines via periodate oxidation and stereoselective reduction to N-substituted syn-4-aryl-4-hydroxy-2-aminobutanoic acids are also described.     

The synthesis of diastereo- and enantiomerically pure beta-aminocyclopropanecarboxylic acids

The synthesis of diastereo- and enantiomerically pure beta-aminocyclopropanecarboxylic acids (beta-ACCs) is described. Starting from pyrrole, (rac)-4 is readily obtained, which was kinetically resolved by enzymatic hydrolysis. Subsequent oxidation of (-)-4 and deformylation gives rise to the cis-beta-ACC derivative (ent)-9, while (+)-10 was converted to the trans-beta-ACC derivative 8. Both 8 and (ent)-9 and their benzyl esters 13 and 16, being conformationally restricted beta-alanine or gamma-aminobutyric acid (GABA) derivatives, represent useful building blocks for peptides containing unnatural amino acids.     

Isolation of stable enantiomerically pure telluroxides and their stereochemistry

Optical resolution of kinetically and thermodynamically stabilized diaryl telluroxides possessing bulky substituents (rac-1a-d) and amino group (rac-2a-c), respectively, by liquid chromatography using optically active columns yielded stable enantiomerically pure telluroxides. The absolute configurations of the optically active telluroxides were determined by comparing their specific rotations and CD spectra with those of sulfur or selenium analogues. The kinetics for the racemization of optically active telluroxides in solution was studied, and it was found that kinetic and thermodynamic stabilization were very effective preventing the racemization of telluroxides. The stabilization energy of telluroxides by intramolecular coordination of the amino group to the tellurium atom was estimated to be ca. 5 kcal mol-1 by variable temperature 1H NMR measurement. The mechanism for the racemization of optically active telluroxides was studied by an isotope experiment using H2(18)O, and the results indicated that optically active telluroxides underwent racemization via an achiral tetracoordinated hydrate.     

Novel chemoenzymatic strategy for the synthesis of enantiomerically pure secondary alcohols with sterically similar substituents

A novel chemoenzymatic strategy for the synthesis of enantiomerically pure secondary alcohols with sterically similar substituents is described. The key step is the kinetic lipase-catalyzed resolution of racemic mixtures of substituted propargylic alcohols. The efficiency of this new approach was tested in the preparation of the corresponding enantiomers of 1,11-hexadecandiol derivatives ((R)-5 and (S)-5). Two strategies were tested. In the first one, the racemic intermediate 1-octyn-3-ol (1) was resolved enzymatically and then elongated with 1-bromo-9,11-dioxadodecane. Alternatively, the racemic 1 can be elongated to the corresponding racemic 17,19-dioxa-7-eicosyn-6-ol (3) first and then resolved biocatalytically. Twelve commercially available lipases were screened for the kinetic resolution of these intermediates. Among them, Candida antarctica lipase (CAL-B) and Humicola lanuginosa lipase (HLL) were the best biocatalysts for the resolution of 1 (S enantiomer 90% ee, E = 35), and 3 (R enantiomer 90% ee, E = 34), respectively.     

Palladium-catalyzed ring expansion reaction of 1-alkynylcyclobutanols with aryl iodides: an efficient route to 2-disubstituted methylenecyclopentanones

The reaction of 1-alkynylcyclobutanols with aryl iodides in the presence of Pd(OAc)₂ and Et₃N in acetonitrile at 80°C for 24 h gives 2-disubstituted methylenecyclopentan-1-ones in modest to good yields. The tandem insertion-ring expansion process proceeds via the formation of an alkynyl π-complex, followed by migration of a carbon-carbon bond of the tert-alkanol to form the cyclopentanones stereoselectively.     

A highly stereoselective and efficient synthesis of enantiomerically pure sitagliptin

A highly stereoselective and efficient synthesis of sitagliptin 1 consisting of a chiral β-amino acid unit has been achieved through 6 steps from commercially available 2,4,5-trifluorobenzaldehyde 4. The chiral antidiabetic drug was obtained with almost perfect enantiomeric purity (>99.9% ee) in 40.9% overall yield. The key feature of the synthesis is the addition of a malonate enolate to a chiral sulfinylimine in more than 99:1 dr. Our synthetic procedure proved to be highly efficient, economical, and sustainable.     

Synthesis of enantiomerically pure P-stereogenic diphosphacrowns and their palladium complexes

A practical synthetic route for enantiomerically pure P-stereogenic diphosphacrowns was developed by using a P-stereogenic bisphosphine as a chiral building block. Their molecular structures were confirmed by NMR spectroscopy and X-ray crystallography. Complexation of the diphosphacrowns with palladium was carried out, and the corresponding palladium complexes were obtained. The P-stereogenic diphosphacrowns were applicable to the chiral ligand for the asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated ketone catalyzed by palladium. This reaction proceeded smoothly to afford the corresponding 1,4-addition products in high yield with good enantioselectivities.     

Unified total synthesis of pteriatoxins and their diastereomers

A unified total synthesis is reported to access all of the possible diastereomers of pteriatoxins A-C, with the use of an intramolecular Diels-Alder reaction as the key step to form the carbo-macrocyclic core structure. The C34/C35-diol protecting groups were found to have significant effects on both the exo/endo-selectivity and the exo-facial selectivity of the intramolecular Diels-Alder process.