On the mechanism of an asymmetric alpha,beta-unsaturated carboxylic acid hydrogenation: application to the synthesis of a PGD2 receptor antagonist

Ruthenium complexes employing axially chiral ligands were found to be effective asymmetric hydrogenation catalysts for the reduction of alpha,beta-unsaturated ene acid 1-E to give 2, a prostaglandin D2 (PGD2) receptor antagonist. With [(S-BINAP)Ru(p-cymene)Cl2]2 (3, S-BINAP = (S)-(+)-2,2'-bis(diphenylphospino)-1,1'-binapthyl), it was discovered that low hydrogen pressures (<30 psi) were essential to achieve high enantioselectivities (92% ee). A detailed mechanistic study was undertaken to elucidate this pressure dependence. It was determined that compound 1-E is in a ruthenium-catalyzed equilibrium with endocylic isomer 1-Endo and in photochemical equilibrium with Z isomer 1-Z. Each isomer could be hydrogenated to give 2, albeit with different rates and enantioselectivities. Hydrogenation of 1-Endo with 3 was found to give 2 in high enantiomeric excess, regardless of pressure and at a rate substantially faster than that of hydrogenation of 1-E and 1-Z. In contrast, isomers 1-E and 1-Z exhibited pressure-dependent enantioselectivities, with higher enantiomeric excesses obtained at lower pressures. A rationale for this pressure dependence is described. Deuterium labeling studies with 1-Endo and tiglic acid were used to elucidate the mechanism of hydride insertion and product release from ruthenium. Under neutral conditions, protonolysis was the major pathway for metal-carbon cleavage, while under basic conditions, hydrogenolysis of the metal-carbon bond was predominant.     

Enantioselective synthesis of a dual orexin receptor antagonist

A concise, enantioselective synthesis of the potent dual orexin inhibitor suvorexant (1) is reported. Key features of the synthesis include a mild copper-catalyzed amination, a highly chemoselective conjugate addition, and a tandem enantioselective transamination/seven-membered ring annulation. The synthesis requires inexpensive starting materials and only four linear steps for completion.     

Synthesis of a potent hNK-1 receptor antagonist via an SN2 reaction of an enantiomerically pure alpha-alkoxy sulfonate

The concise synthesis of a stereochemically rich hNK-1 receptor antagonist is described. The synthesis is highlighted by an S(N)2 reaction of an enantiomerically pure alpha-alkoxy sulfonate (orthogonally protected butane triol), which was prepared by utilizing salen-mediated hydrolytic kinetic resolution technology. A stereocontrolled acetalization was employed to connect two enantiomerically pure fragments with a high degree of diastereoselectivity.     

Enantioselective, protecting group-free synthesis of 1S-ethyl-4-substituted quinolizidines

A practical enantioselective protecting group-free four-step route to the key quinolizidinone 6 from phenylglycinol-derived bicyclic lactam 1 is reported. The Grignard addition reaction to 6 takes place stereoselectively to give 1-ethyl-4-substituted quinolizidines 4-epi-207I and 7-9. Following a similar synthetic sequence, 9a-epi-6 is also accessed. However, the addition of Grignard reagents to 9a-epi-6 proceeds in a non-stereoselective manner. In order to gain insight into the different stereochemical outcome in the two series, theoretical calculations on the iminium salts A and B have been performed. The study concludes that the addition of the hydride, which is the step that determines the configuration of the final products, occurs in a stereoelectronic controlled manner. The theoretical study is in agreement with the experimental results.     

Enantioselective synthesis of 3-demethoxyaranciamycinone via asymmetric epoxidation

The tetracyclic olefin 1 was enantioselectively epoxidized using a molybdenum(VI)- oxodiperoxo complex containing a chiral lactamide. Conversion to the glycosides 8 and 9 showed the epoxide 2 to be the predominant (3 : 1) enantiomer.     

A convenient two step protocol for the synthesis of cyclopentenones and indanones,including an asymmetric variant

A one-pot palladium mediated hydrostannylation/cross-coupling protocol is used to give direct access to cross-conjugated dienones that can be utilized in Nazarov cyclizations to afford highly substituted cyclopentenones and indanones, including an asymmetric variant.     

Enantioselective reduction of benzofuryl halomethyl ketones: asymmetric synthesis of (R)-bufuralol

Enantioselective reduction of representative 2-(bromoacetyl)- and 2-(chloroacetyl)benzofurans with (−)-B-chlorodiisopinocampheylborane and by transfer hydrogenation with formic acid/triethylamine in the presence of RhCl[R,R-TsDPEN](C₅Me₅) is described. Transfer hydrogenation of the chloro ketones produced the corresponding chlorohydrins of ⩾95% ee. (R)-Bufuralol of 96% ee was prepared from the corresponding chloro ketone by transfer hydrogenation–substitution.     

Asymmetric synthesis of 3-substituted isoindolinones: application to the total synthesis of (+)-lennoxamine

An anionic chiral auxiliary mediated asymmetric alkylation of carbamate 2 provides 3-substituted isoindolinones 4 in high ee. This methodology was used in the first asymmetric synthesis of (+)-lennoxamine.     

Enantioselective synthesis of optically active secondary amines via asymmetric reduction

The enantioselective synthesis of optically active secondary amines via the asymmetric reduction of N-substituted ketimines with various chiral hydride reagents, such as Itsuno's reagent (1), Corey's reagent (2), K glucoride (3), Sharpless' reagent (4), and Mosher's reagent (5) has been investigated. Among the hydride reagents examined, 1 gave the best results in terms of asymmetric induction. Thus, the reduction of N-phenylimine derivatives of aromatic ketones with 1 provided the corresponding amines in 96–98% yields with high optical induction, such as 73 % ee for acetophenone N-phenylimine (6a), 87 % ee for propiophenone N-phenylimine (6b), 88 % ee for bulyrophenone N-phenylimine (6c), and 71 % ee for isobutyrophenone N-phenylimine (6d). In the case of N-alkyl ketimine derivatives, the reduction afforded somewhat lower optical inductions as compared to those of N-phenyl derivatives, giving 46 % ee for acetophenone N-benzylimine (6f), 52 % ee for acetophnone N-ⁿ-heptylimine (6g) and 43 % ee for acetophenone N-cyclohexylimine (6h). However, the substitution of a bulky alkyl group on nitrogen of the ketimines increases remarkably the optical induction of product amine, such as 80 % ee for acetophenone N-tert-butylimine (6e). The reduction of N-substituted aliphatic ketimines gave very low optical inductions (7.4 – 24 % ee). The catalytic effects of oxazaborolidines (1a and 2a) in the reduction of ketimines with 1 and 2 were also examined.     

[4+2] Cycloaddition of 1-aminodienes and 2-substituted vinylphosphonates: application to asymmetric synthesis of 3-amino-5-phosphono-1-cyclohexene derivatives

N-Butadienylsuccinimide (1), iso-propyl N-butadienyl-(S)-pyroglutamate (5) and N-butadienyl-(R)-4-phenyloxazolidin-2-one (6) reacted with vinylphosphonates, vicinally-substituted (2) by electronwithdrawing groups (CO₂Me, CN, COMe), to furnish [4+2] cycloadducts (3-4,7-10, and 11-14) in moderate to good yields (40-88%). The reactions were highly selective: regioselectivity of 95-100%, endoselectivity of 75-92% and facial selectivity of 80-95%. The major diastereoisomers were fully characterized by ¹H and ¹³C NMR spectroscopy.     

Practical asymmetric synthesis of a non-peptidic alphavbeta3 antagonist

The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite beta-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.     

Enantioselective synthesis of primary 1-(aryl)alkylamines by nucleophilic 1,2-addition of organolithium reagents to hydroxyoxime ethers and application to asymmetric synthesis of G-protein-coupled receptor ligands

(E)-Arylaldehyde oxime ethers bearing a (1S)-2-hydroxy-1-phenylethyl or (2R)-1-hydroxy-2-phenylethyl group as a chiral auxiliary, both derived from a single precursor, methyl (R)-mandelate, underwent nucleophilic addition with organolithium reagents via six-membered chelates to give the diastereomerically enriched (R)- and (S)-adducts, respectively, which, after chiral auxiliary removal by reductive N-O bond cleavage, led to the corresponding (R)- and (S)-1-(aryl)ethylamines. This organolithium addition protocol using methyllithium was applied in an enantiodivergent fashion to the preparation of both enantiomers of 1-(2-hydroxyphenyl)ethylamine, which has been previously used as an efficient chiral auxiliary for the synthesis of natural products in this laboratory. The synthetic utility of this methodology involving diastereoselective methyl addition was demonstrated by further application to the asymmetric synthesis of a new type of calcium receptor agonist (calcimimetics), (R)-(+)-NPS R-568 and its thio analogue. Furthermore, diastereoselective vinylation was accomplished by application of the hydroxy oxime ether-based protocol using vinyllithium, which allowed the development of the enantioselective synthesis of the NK-1 receptor antagonists, (+)-CP-99,994 and (+)-CP-122,721.     

Dynamic thermodynamic resolution: solvent effects, mechanism, and an asymmetric 3,4,5-substituted benzazepine synthesis

[reaction: see text] The resolution in the lithiation-substitution sequence from 1 to 4-11 in MTBE is shown to be under thermodynamic control in contrast to the previous report of kinetic control in diethyl ether. Diastereomeric equilibration of a soluble complex is shown to be controlling and an asymmetric synthesis of a 3,4,5-substituted benzazepine is reported.     

New chlorinated cyclopentenones prepared from hexachlorocyclopentadiene: synthesis,chemical properties,and application in the synthesis

The review surveys chemical conversions of 5-substituted 2,3,5-trichloro-4,4-dimethoxycyclopent-2-en-1-ones and related compounds and the possibilities of their use in the synthesis.     

Organocatalytic asymmetric 5-hydroxypyrrolidine synthesis: a highly enantioselective route to 3-substituted proline derivatives

The highly enantioselective organocatalytic tandem reaction between 2-acylaminomalonates and α,β-unsaturated aldehydes is presented. The reaction is a direct entry to 5-hydroxypyrrolidines and 3-substituted proline derivatives, which are furnished in high yields and 90-99% ee.     

Enantioselective synthesis of 1-aryl-tetrahydroisoquinolines through iridium catalyzed asymmetric hydrogenation

Asymmetric hydrogenation of 1-aryl-3,4-dihydroisoquinolines using the [IrCODCl](2)/(R)-3,5-diMe-Synphos catalyst is reported. Under mild reaction conditions, this atom-economical process provides easy access to a variety of enantioenriched 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives, which are important pharmacophores found in several pharmaceutical drug candidates, in high yields and enantiomeric excesses up to 99% after a single crystallization.     

Intramolecular Michael reaction of tert-butylsulfinyl ketimines: asymmetric synthesis of 3-substituted indanones

Aromatic tert-butylsulfinyl ketimines bearing a suitable Michael acceptor at the ortho position readily undergo an intramolecular conjugate addition achieving indanone derivatives in good yields and complete diastereoselectivity.