A catalytic and stoichiometric approach to the synthesis of the steroid B-ring en route to estratrienes

Zirconocene catalyzed cyclization of 2-(5-methoxy-3-penten-1-yl)styrene in the presence of organomagnesium reagents was studied. The cyclization proceeded in high isolated yields (up to 84%) with excellent trans-selectivity (>98%), which is unusual for the formation of cyclohexane derivatives. Catalytic cyclization in the presence of Cp₂ZrCl₂ proceeded as well with similar results. The reaction with (R,R)-(EBTHI)₂ZrCl₂ gave a cis/trans mixture of 5 in low yield and poor ee.     

Enantioselective imine Michael reaction for the preparation of the (8′R,8a′S)-8,8a′-dimethyl-1′,3′,4′,7′,8′,8a′-hexahydrospiro[1,3-dioxolane-2,2′(6′H)naphthalen]-6′-one building block. A formal synthesis of (+)-valencenol

The enantioselective Michael addition of a chiral imine of 4-protected 2-methylcyclohexane-1,4-dione to phenyl crotonate led after cyclization to the corresponding bicyclic lactam. Reductive cleavage of the chiral moiety followed by saponification gave the corresponding keto-acid, which was cyclized to afford a lactone. Belleau–Fujimoto reaction of the lactone then led to the title building block (diastereoselectivity 96:4, e.e. >98%) in 11% overall yield from the starting dione. (8R,8aS)-(+)-8,8a-Dimethyl-3,4,6,7,8,8a-hexahydronaphthalen-2(1H)-one was obtained after reduction of the carbonyl group, acetylation, and reductive cleavage–deprotection (52% overall yield), representing a formal synthesis of (+)-valencenol.     

A variation of the Pictet-Spengler reaction via a sequential reduction-cyclization reaction of N-acylcarbamates: synthesis of 1-substituted tetrahydroisoquinoline derivatives

A new variation of the Pictet-Spengler reaction for the synthesis of 1-substituted tetrahydroisoquinoline derivatives has been developed. The reaction employs the reduction of N-acylcarbamates by DIBAL-H followed by simultaneous cyclization mediated by BF₃·OEt₂. The synthetic potential of this method has been illustrated by the synthesis of the tetrahydroisoquinoline alkaloids, (±)-xylopinine, (±)-laudanosine, (±)-8-oxo-O-methylbharatamine, and (±)-isoindoloisoquinolone.     

Novel and enantioselective syntheses of (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid: a synthon for sitagliptin and its derivatives

A new synthetic strategy for (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid, a building block in the preparation of sitagliptin and its derivatives, was developed. Pd(OAc)₂ catalyzed coupling of 2,4,5-trifluoro-1-iodobenzene with allyl alcohol gave 3-(2,4,5-trifluorophenyl)propanal in a yield of 95%. l-Proline catalyzed reaction of the 3-phenylpropanal (in only 1.2 molar equiv) with nitrosobenzene followed by reduction with NaBH₄ and Pd/C catalyzed hydrogenation gave (R)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >99% ee and 65% yield. Selective tosylation of primary hydroxyl group of the 1,2-propandiol unit followed by cyanide displacement afforded (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanenitrile (80%). The nitrile was converted to the title β-hydroxy acid under basic hydrolysis in a yield of 90%. Thus, (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid was prepared enantioselectively from the starting material in four steps and 45% overall yield. The reaction sequence was repeated with d-proline as the catalyst to give (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid in 45% overall yield and >99% enantiomeric excess.     

A concise and stereoselective synthesis of (+/−)-erythro-methylphenidate

A concise and stereoselective synthesis of racemic erythro-methylphenidate (1) is described. The coupling reaction between piperidine-2-thione (3) and 2-bromo-2-phenylmethylacetate (4) afforded the β-enaminocarbonyl compound 2 in 60% yield by a modified Eschenmoser sulfide contraction reaction. In most cases the bicyclic thiazolidinone 5 was produced. Diastereoselective reduction of 2 in the presence of borohydrydes furnished the (+/−)-erythro-methylphenidate in good yields with dr >95%.     

A new titanate/(+)-(1R,2S)-cis-1-amino-2-indanol system for the asymmetric synthesis of (S)-tenatoprazole

Tenatoprazole, a substituted imidazopyridinyl derivative, is an irreversible proton pump inhibitor (PPI), which is used for the prevention and treatment of gastric acid-related diseases. A new highly efficient asymmetric oxidation using cumene hydroperoxide (CHP) as the oxidant in the presence of titanium tetraisopropoxide (Ti(OiPr)₄) and (+)-(1R,2S)-cis-1-amino-2-indanol, in a polar aprotic solvent at 0-20 °C, has been developed to prepare tenatoprazole with an enantiomeric excess of >99%, a chemoselectivity of >90% and a chemical yield of >90% from the corresponding sulfide. This procedure was successfully implemented on scales ranging from 100 mg to multiple kilograms. Detailed studies of the parameters controlling purity and yield for this reaction are presented.     

A practical enantioselective total synthesis of (−)-(S)-stepholidine

A convergent enantioselective total synthesis of (−)-(S)-stepholidine, a drug candidate for the treatment of schizophrenia and/or drug abuse, was described, which represented the first example of successful auxiliary-assisted Bischler–Napieralski cyclization of amide bearing bromine atom at 2-position of the C ring, followed by an introduction of the aryl methyl ester via Br–Li exchange. (−)-(S)-Stepholidine was synthesized in 6 steps, with 52% overall yield and >99% ee. The reported synthesis is practically free from chromatographic separation.     

Facile ring-closure cyclization of arenes by nucleophilic C-alkylation reaction in ionic liquid

A novel synthetic method using an ionic liquid (IL) for a six-membered ring-closure cyclization is described. The ring-closure cyclization by nucleophilic C-alkylation was achieved with various halo- and alkanesulfonyloxyalkyl aromatic compounds in high yields with minimal byproducts using ILs as the reaction media in the absence of any catalyst. For example, the cyclization of 2-(3-methanesulfonyloxy-propoxy)naphthalene (1a) to 2,3-dihydro-1H-naphtho[2,1-b]pyran (2) in IL [bmim][PF₆] proceeded selectively at 150 °C for 24 h in 85% yield.     

Dirhodium catalyzed intramolecular enantioselective C–H insertion reaction of N-cumyl-N-(2-p-anisylethyl)diazoacetamide: synthesis of (−)-Rolipram

Cumyl(2,2-dimethyl-benzyl) was used as an N-protecting group for intramolecular C–H insertion reaction of α-diazoacetamide. Excellent chemoselectivity (>98:2) in C–H insertion over the aromatic addition of N-cumyl-N-(2-p-anisylethyl)diazoacetamide was obtained with Rh₂[(4S)-MEOX)]₄ catalyst in moderate enantioselectivity (53% ee). The reaction was successfully applied in the synthesis of (−)-Rolipram in 15% total yield.     

Cyclization of N,N-diethylgeranylamine N-oxide in one-pot operation: preparation of cyclic terpenoid-aroma chemicals

Acid promoted cyclization of the geranylamine N-oxide (E)-4 followed by base-catalyzed intramolecular aldol condensation afforded 1-acetyl-4,4-dimethyl-1-cyclohexene (7) in one-pot operation. Reduction of 7, which possess strong fruity odor, followed by lipase-catalyzed kinetic resolution furnished the acetate (R)-26 (>49.9% yield, >99% ee) and the recovered alcohol (S)-25 (>49.9% yield, >99% ee, herbal odor).     

Acid catalyzed monodehydro-2,5-diketopiperazine formation from N-α-ketoacyl amino acid amides

We have developed a new synthetic method for monodehydro-2,5-diketopiperazines (monodehydroDKPs), which is based on an acid catalyzed cyclization of N-α-ketoacyl amino acid amides. Using this cyclization reaction, monodehydroDKP was formed with no or slight racemization in case that N-α-ketoacyl amino acid amides with β-aliphatic-α-ketoacyl groups and sterically unhindered N-substituting groups at the C-terminal amide nitrogen were used in the presence of catalytic amount of p-TsOH (3-5 mol %) or 10% TFA. In the case of β-aryl-α-ketoacyl amino acid derivatives, in which an enol form predominantly exists by conjugation with the aromatic ring, racemization could be minimized by optimizing the reaction conditions (5 mol % p-TsOH, reflux for 6 h), although the chemical yield could not be dramatically improved. However, this reaction condition was successfully applied to the synthesis of a tubulin depolymerization agent, (−)-tert-butyl-oxa-phenylahistin, with no racemization.     

Versatile synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans and 1H-isochromenes by palladium-catalyzed cycloisomerization of 2-alkynylbenzyl alcohols

An easy synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans and 1H-isochromenes by palladium-catalyzed cycloisomerization of readily available 2-alkynylbenzyl alcohols under neutral conditions is reported. Reactions were carried out at 70-100°C in the presence of catalytic amounts (1-2%) of PdI₂ in conjunction with 2 equiv. of KI for 1.5-24 h. The preference towards the 5-exo-dig cyclization mode (leading to 1,3-dihydroisobenzofurans) or the 6-endo-dig cyclization mode (leading to isochromenes) turned out to be dependent on the substitution pattern of the substrate as well as reaction conditions. In several cases, by properly adjusting the reaction conditions, the same substrate could be selectively converted into either the dihydroisobenzofuran or the 1H-isochromene derivative.     

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.     

Parallel or classical kinetic resolution of a planar chiral ferrocenylketone through asymmetric reductions

Racemic 1-acetyl-2-methoxymethylferrocene, (±)-1 was subjected to asymmetric reduction with two different methodologies and complementary results were obtained. When the reduction of (±)-1 was carried out in the presence of CBS-oxazaborolidine catalyst and BH₃·Me₂S as the hydrogen source, both enantiomers of the substrate were converted with comparable reaction rates and selectivities. The corresponding diastereoisomeric ferrocenylalcohols 3a and 3b were obtained in a 1:1 ratio and >90% enantiomeric excess; this reaction profile being related with a parallel kinetic resolution with high ds₁ and ds₂ diastereofacial selectivities. On the contrary, the transfer hydrogenation of (±)-1 with HCOOH/triethylamine in the presence of (R,R)-Noyori’s catalyst proceeded via classical kinetic resolution, so that the formed (?)-3b or unreacted (+)-1 could be obtained in highly enantiopure form before or beyond 50% of the substrate conversion, respectively. Alcohol 3b with an (1R_p,S)- or (1S_p,R)-configuration is not easily accessible by the diastereoselective metallation/electrophilic quenching sequence routinely applied in the synthesis of planar chiral ferrocenes. As a result, the described procedures provide a valuable access to this useful starting material for the synthesis of homochiral related derivatives.     

An efficient and convergent synthesis of the potent and selective H3 antagonist ABT-239

An efficient and convergent process for the preparation of a potent and selective H₃ receptor antagonist, ABT-239, 1A was accomplished with an overall yield of 64%. The key step in the synthesis is a Sonogashira coupling/cyclization reaction of 1-but-3-ynyl-2-(R)-methylpyrrolidine (9) with 4′-hydroxy-3′-iodo-biphenyl-4-carbonitrile (3). Additionally, the key amine component 2-(R)-methylpyrrolidine (7) was effectively synthesized from the readily available Boc-l-prolinol with a simple catalytical hydrogenolysis as the key step. This column chromatography-free process is highlighted by several simple work-up and purification procedures and is amendable to the large-scale preparation of 1A.     

Novel and Stereospecific Synthesis of (2S)‐3‐(2,4,5‐Trifluorophenyl)propane‐1,2‐diol from D‐Mannitol

A stereospecific synthesis of (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol from D ‐mannitol has been developed. The reaction of 2,3‐O‐isopropylidene‐D ‐glyceraldehyde with 2,4,5‐trifluorophenylmagnesium bromide gave [(4R)‐2,2‐dimethyl‐1,3‐dioxolan‐4‐yl](2,4,5‐trifluorophenyl)methanol in 65% yield as a mixture of diastereoisomers (1 : 1). The Ph₃P catalyzed reaction of the latter with C₂Cl₆ followed by reduction with Pd/C‐catalyzed hydrogenation gave (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol with >99% ee and 65% yield.     

Facile and efficient synthesis of polyfunctionalized benzofurans: three-component coupling reactions from an alkynylsilane, an o-hydroxybenzaldehyde derivative, and a secondary amine by a Cu(I)-Cu(II) cooperative catalytic system

The combination of 5 mol % Cu(OTf)₂ and CuCl in the presence of DMAP effectively catalyzed a three-component coupling reaction involving an alkynylsilane, an o-hydroxybenzaldehyde derivative, and a secondary amine. The reaction proceeded via intramolecular 5-exo-dig cyclization, resulting in direct synthesis of the corresponding benzofuran derivatives in moderate to excellent yields.     

Ruthenium-catalyzed intramolecular cyclization of hetero-functionalized allylbenzenes

Intramolecular addition of heterofunctionalities to CC double bonds without β-hydride elimination was investigated and catalyzed by ruthenium complexes. The combination of RuCl₃ · nH₂O (10 mol%) and 3 equiv. of AgOTf acted as a catalyst for cyclization of 2-allylphenol (1a) to 2,3-dihydro-2-methylbenzofuran (2a) in good yield in the presence of Cu(OTf)₂ as a co-catalyst and PPh₃ as a ligand. This catalyst system also catalyzed the cyclization of 2-allylbenzoic acid to lactone in 91% yield. Then, a new catalyst system (RuCp¹Cl₂)₂ (1.0 mol%)/4AgOTf/4PPh₃, was found to be more active even in the absence of Cu(OTf)₂. Furthermore, this catalysis was applied to asymmetric reaction of 2-allylphenol (1a). When using TolBINAP as a ligand, over 60% e.e. was achieved.     

A novel cyclization/oxidation strategy for a two-step synthesis of (Z)-aurone

An efficient and facile two-step strategy for the synthesis of (Z)-aurone from arylacetylenes and salicyladehydes, via silver(I) nitrate mediated cyclization/oxidation in the presence of potassium carbonate has been developed. The key feature of our method was delicate cascade reaction, to provide the corresponding (Z)-aurone in high yield and good regio- and stereo selectivity.     

The first total synthesis of (±)-zenkequinone B

The first total synthesis of tetrahydrobenzo[a]anthraquinone natural product (±)-zenkequinone B (1) is reported. The key step involves the TiCl₄-promoted intramolecular cyclization of 4-aryl-2-hydroxybutanal diethyl acetal 4 to give compound 3. The total synthesis of (±)-zenekequinone B (1) has been accomplished in five steps from readily available 2-(chloromethyl)-9,10-dimethoxyanthracene (5) in 40.3% overall yield.