Synthesis of enantiopure structured triacylglycerols

The synthesis of nine enantiopure structured triacylglycerols (TAGs) of the AAB type is described, all possessing the (S)-absolute configuration. Six of them possess one saturated and two identical unsaturated fatty acyl chains, whereas the remaining three possess two identical saturated fatty acids along with one unsaturated fatty acid. The former group was synthesized by a five-step chemoenzymatic route involving a highly regioselective immobilized Candida antarctica lipase, starting from enantiopure (R)-solketal. The second group was prepared by a fully chemical five-step approach based on the same chiral precursor. Such enantiopure TAGs are strongly required as standards for the enantiospecific analysis of intact TAGs in fats and oils.     

Synthesis of enantiopure ethyl deoxymonate B from allylic sulfinyl dihydropyrans

A completely stereoselective dihydroxylation of a dihydropyranol and a cross-metathesis in the presence of a free homoallylic hydroxyl group are the key steps of a synthesis of enantiopure ethyl deoxymonate B from a sulfinyl dienol.     

Synthesis of enantiopure 3-substituted morpholines

Enantiopure 3-substituted morpholines were assembled through ring-opening of a N-2-benzothiazolesulfonyl (Bts) activated aziridine with organocuprates followed by a ring annulation reaction with a vinylsulfonium salt under microwave conditions. Deprotection of the N-Bts group proceeds under very mild conditions with 2-mercaptoacetic acid and LiOH at rt.     

Synthesis of novel enantiopure fluorinated building blocks from acyclic chiral allylsilanes

[reaction: see text] Homochiral beta-fluorinated gamma,delta-unsaturated carboxylic acids with an allylic fluorinated stereogenic center are available from the corresponding enantiopure allylsilanes. The key step for introduction of the fluorine substituent is an electrophilic fluorodesilylation reaction carried out in the presence of Selectfluor. Reduction of the resulting beta-fluorinated pentenoic acid into the corresponding fluorinated alcohol was also performed leading to the formation of an enantiopure second-generation fluorinated building block.     

Synthesis of enantiopure vicinal diaminoesters and ketopiperazines from N-sulfinylimidazolidines

A short and efficient synthesis of mono- and bicyclic ketopiperazines bearing methoxycarbonyl substituents is described. The route entails selective protection and solvolysis of N-sulfinylimidazolidines to provide vicinal diaminoesters with the nitrogen atoms suitably differentiated. Then, an N-acylation/cyclization protocol renders the ketopiperazines. In addition a diastereoselective route to an analog of the natural diketopiperazine DKP 593A through a 2-piperidinylglycinate available by this method is described.     

Synthesis of functionalised enantiopure steroids from estrone and cholestanone through organolithium intermediates

The reaction of epoxides 1 and 8 derived from estrone and cholestanone, respectively, with an excess of lithium and a catalytic amount of DTBB (7 mol%) in THF at −78°C led to formation of the corresponding β-oxido-functionalised organolithium intermediates 2 and 9, respectively, in a regio- and stereoselective manner. Treatment of these intermediates with different electrophiles [H₂O, D₂O, PhCHO, Me₂CO, Et₂CO, (CH₂)₅CO, CO₂] at −78 to 20°C afforded, after hydrolysis with water, enantiomerically pure derivatives 3 and 10, respectively. When protected ketones 5 and 6 derived from d-glucose and d-fructose were used as the electrophile, the reaction with 2 gave the expected mixed products 3g and 3h, respectively, which consist of a steroid and a carbohydrate fragment. The reaction of O-protected estrone 4 as the electrophilic component and intermediate 2 afforded the C₂-symmetric steroid dimer 3f. The stereochemistry of the products was unambiguously determined by correlation with X-ray data for compound 3d and by comparison with the known compound 6a. Finally, the addition of the dianions 13, resulting from the DTBB-catalysed lithiation of phthalan 12a and isochroman 12b, to the O-protected estrone 4 and to cholestanone 9 led to the formation of the diols 14, 15 and 16. Diols 14 were cyclised under Mitsunobu reaction conditions to the corresponding heterocycles 17.     

Synthesis of highly substituted enantiopure piperazines and ketopiperazines from vicinal N-sulfinyl diamines

Enantiopure 1-benzyl-2,3-disubstituted piperazines (4) have been synthesized by treatment of N-sulfinyl-N-benzyldiamino alcohols (1) with diethyl oxalate and sodium methoxide followed by reduction with borane. Alternatively, the sulfinamido group was preserved by an N-acylation/cyclization protocol using alpha-chloroacetyl chloride that led to the synthesis of N-sulfinyl ketopiperazines (11). Ensuing elimination of the sulfinyl group with NaH produced imino ketopiperazines (9) that are suitably functionalized for nucleophilic addition to the imino moiety. Stereoselective and high yielding allylation of imino ketopiperazines (9c) was achieved under Barbier conditions using CeCl3.7H2O as the additive.     

Synthesis of enantiopure 2-C-methyl-D-erythritol 4-phosphate and 2,4-cyclodiphosphate from D-arabitol

[reaction: see text] Two key intermediates of the newly discovered mevalonate-independent pathway for isoprenoid biosynthesis were prepared. Optically pure 2-C-methyl-D-erythritol 4-phosphate and 2,4-cyclodiphosphate were chemically synthesized from D-arabitol using a convenient benzylidene and tert-butyldimethylsilyl protection of polyhydroxylated intermediates. The new scheme offers a straightforward route to analogues and labeled forms.     

Synthesis of enantiopure omega-functionalized C15 alpha-amino carboxylates

An efficient route for the synthesis of enantiopure omega-hydroxy, omega-carboxy, omega-oxo, and omega-amino alpha-amino acids and bis-alpha-amino acids was developed. The synthesis of omega-trityloxy delta,epsilon-unsaturated alpha-amino acids was based on the Wittig reaction of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxopentanoate with omega-trityloxy alkylidene triphenylphosphoranes. After hydrogenation, the omega-hydroxy alpha-amino acid was used as starting material for the synthesis of other omega-functionalized alpha-amino acids. The length of the side chain of alpha-amino acids or bis-alpha-amino acids depends on the starting alkanediol or dibromide used to prepare the phosphoranes.     

Synthesis of enantiopure B-nor-steroids by multiple Pd-catalyzed transformations

The synthesis of the novel enantiopure B-nor-steroid 9 is described employing a combination of a Suzuki- and a Heck-reaction. As substrates the 2-bromobenzylchloride (11) and the boronic ester 16 were used; the latter was prepared from the Hajos-Wiechert ketone derivative 17 in five steps. Noteworthy, the Heck-reaction was performed under microwave irradiation, which was much superior compared to the normal thermal reaction. The purpose of the described work is the design of novel estrogens, which bind to the β-unit of the maxi K⁺-channel located on the surface of the endothelium without showing the hormonal activity of estradiol 6.     

Synthesis and axial chirality of an enantiopure aminodibenzazepinone

A route for the synthesis of (S,S)-7-amino-5-methyl-5H-dibenzo[b,d]azepin-6(7H)-one hydrochloride is disclosed. The synthesis includes a Friedel–Crafts alkylation to form the seven-membered ring and a highly efficient classical resolution. Additional studies on the enantiopure material showed the amine to be highly resistant to racemization, which led us to investigate the unexpected stability. We propose that the inherent axial chirality contained in the dibenzazepinone works to produce an interesting chirality transfer mechanism, which accounts for the observed robustness of the stereocenter. This previously unrecognized stereochemical element exists within this specific class of molecules, and they should be drawn in a manner which displays the axial chirality.     

Synthesis of enantiopure cis-decahydroquinolines from homotyramines by Birch reduction and aminocyclization

Birch reduction of homotyramines with a syn-β-amino alcohol unit followed by acid treatment of formed dihydroanisole derivatives gives polysubstituted enantiopure cis-decahydroquinolines. The stereoselectivity of the process differs if the hydroxyl group is free or protected. The procedure allows the synthesis of 7-oxodecahydroquinolines embodying four stereogenic centres with the same relative configuration as that of lepadins F and G.     

Synthesis of enantiopure chloroalcohols by enzymatic kinetic resolution

3-Alkenyl and heteroaryl chloroalcohols have been obtained in excellent enantiomeric excess (>99%) by enzymatic kinetic resolution using the haloalcohol dehalogenase HheC. Yields were close to the theoretical maximum for all substrates employed. Furthermore, the applicability of this methodology on multigram scale has been established.     

Synthesis of new enantiopure trans-3,4-diaminocaranes from (+)-3-carene

A synthetic strategy to obtain new enantiopure trans-3,4-diaminocaranes derived from (+)-3-carene via a stereoselective methodology is described. The stereoselective preparation of 3,4-α-carene- or 3,4-β-carene-epoxide is followed by a ring opening by sodium azide to obtain the azido-alcohols. Subsequent cyclization affords the corresponding aziridine diastereoisomers, which are converted to azido amines by opening of the aziridine rings by sodium azide and then reduced to the final diamine diastereoisomers. The absolute configurations of the final diamines and of novel intermediates are established by ¹H NMR spectra correlated with conformational analysis supported by molecular modeling.     

Synthesis of enantiopure cyclobutane amino acids and amino alcohols

(−)-(1R,3S)-3-Amino-2,2-dimethylcyclobutanecarboxylic acid and (+)-(1R,3S)-3-amino-2,2-dimethylcyclobutylmethanol, which can be used to prepare enantiopure oligopeptides and cyclobutane-based carbocyclic nucleosides, were synthesized from (+)-(1R)-α-pinene.     

Synthesis of highly functionalised enantiopure bicyclo[3.2.1]- octane systems from carvone

The commercially available monoterpene carvone has been efficiently converted into the tricyclo[3.2.1.0(2.7)]octane and bicyclo[3.2.1]octane systems characteristic of some biologically active compounds. The sequence used for this transformation involves as key features an intramolecular Diels-Alder reaction of a 5-vinyl-1,3-cyclohexadiene and a cyclopropane ring opening.     

Synthesis of enantiopure cis- and trans-2,3-disubstituted piperidines

The synthesis of enantiopure cis- and trans-2,3-disubstituted piperidines 4 is described. The key step of the synthesis involves the stereoselective reduction of chiral nonracemic lactams 2 by using BH3.Me2S. A rationalization of the stereoselectivity is presented.     

Synthesis of enantiopure helical cyclophanes containing five-membered heterocyclic rings

The preparation of optically active (S)-(+)-4-(2-propenyl)[2.2]paracyclophane 1b is described. Cycloaddition reactions of this diene with N-phenylmaleimide 2 and maleic anhydride 5 were carried out under high pressure conditions. The cycloadducts were converted into optically active heterohelicenophanes. A systematic ¹H and ¹³C NMR spectroscopic analysis of the reaction products is also presented.     

Improved synthesis of tert-butanesulfinamide suitable for large-scale production

[reaction: see text] An improved synthesis of tert-butanesulfinamide that overcomes the scalability problems of the previous syntheses is described. The key step is the catalytic asymmetric oxidation of the inexpensive di-tert-butyl disulfide starting material. The new homogeneous reaction conditions utilize an inexpensive chiral ligand prepared in a single step from commercially available cis-1-amino-indan-2-ol. The reaction is performed at a 2.3 M concentration in the practical solvent acetone and can readily be run on a kilogram scale.