Stereoselective synthesis of (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile.

(S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966, (1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford ß-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S(N)2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1'-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.

Asymmetric hydrogenation catalyzed by a rhodium complex of (R)-(tert-butylmethylphosphino)(di-tert-butylphosphino)methane: scope of enantioselectivity and mechanistic study.

The rhodium complex of (R)-(tert-butylmethylphosphino)(di-tert-butylphosphino)methane used in Rh-catalyzed asymmetric hydrogenation of representative substrates 3-14 demonstrated high catalytic activity coupled with wide scope and nearly perfect enantioselectivity. Mechanistic studies (NMR and DFT computations) were carried out in order to investigate the mechanism of the enantioselection in the asymmetric hydrogenation of (Z)-alpha-acetamidocinnamate (3). Although catalyst-substrate complexes 15a,b with the double bond coordinated near the non-"chiral" phosphorus atom were formed as kinetic products upon the addition of 3 to solvate complex 2 at -100 degrees C, they rapidly rearranged to more stable isomers 15c,d with the double bond coordinated near the "chiral" phosphorus atom. The thermodynamic and kinetic parameters of the interconversion between 15c and 15d were determined by NMR; mainly, the interconversion occurred intramolecularly via nonchelating catalyst-substrate complexes 16. The equilibrium between 15d and 16d was directly observed from NMR line shape changes at temperatures ranging from -100 to -40 degrees C, whereas no such equilibrium was observed for 15c. This result was accounted for computationally by determining the corresponding transition states for the methanol insertion into 15c,d. Three sets of experiments of the low-temperature hydrogenation of different catalyst-substrate complexes gave the same order and sense of enantioselectivity (97% ee (R)) even in the case when 15c, having Re-coordinated double bond, was hydrogenated under the conditions precluding its isomerization to 15d. It was concluded that the hydrogenation of 15c,d does not occur directly, but is preceded by the dissociation of the double bond to result in the more reactive species 16. This indicates that enantioselection must occur at a later step of the catalytic cycle. DFT computations of association and migratory insertion steps suggest that enantioselection takes place during the association step when chelating dihydride 19d.MeOH is formed from nonchelating dihydride 18d.

Highly enantioselective asymmetric hydrogenation of beta-acetamido dehydroamino acid derivatives using a three-hindered quadrant rhodium catalyst.

[reaction: see text] A previously reported three-hindered quadrant chiral ligand and its corresponding rhodium complex provide high enantioselectivity for the asymmetric hydrogenation of beta-acetamido dehydroamino acid substrates. Both (E)- and (Z)-substrates are hydrogenated with high enantioselectivity in all of the reported examples. Asymmetric hydrogenation of a cyclic beta-acetamido dehydroamino acid substrate in 85% ee is also reported.

A highly enantioselective allylic amination reaction using a commercially available chiral rhodium catalyst: resolution of racemic allylic carbonates.

A novel method for the kinetic resolution of unsymmetrical acyclic allylic carbonates and the concurrent synthesis of enantioenriched secondary amines using a commercially available chiral catalyst is disclosed.

Rational design and synthesis of 4-((1R,2R)-2-hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a novel, nonsteroidal androgen receptor antagonist devoid of phototoxicity for dermatological indications.

4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.

Stereoselective cyclization and pyramidal inversion strategies for P-chirogenic phospholane synthesis.

Preparation of P-chirogenic mono- and bisphospholanes is reported. The demonstrated method employs a stereoselective cyclization of cyclic sulfates with primary phosphines in the presence of base to generate "cis" or "cis/cis" P-chirogenic phospholanes followed by heat-induced pyramidal inversion to provide "trans" or "trans/trans" P-chirogenic phospholanes. A rhodium complex of one "trans/trans" phospholane is applied to the highly enantioselective asymmetric hydrogenation of a substrate precursor to the pharmaceutical candidate pregabalin.

Synthesis of both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand via convergent routes and application to rhodium-catalyzed asymmetric hydrogenation of CI-1008 (pregabalin).

Both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand are synthesized via two convergent methods. The first method relies on the chiral alkylation of 1-((-)-menthoxy)phospholaneborane using a s-BuLi/(-)-sparteine derived chiral base. Only one enantiomer of the catalyst could be synthesized via this method because only one antipode of sparteine is available in nature. The second route relies on the combination of methylphosphine borane and a chiral 1,4-diol. Either enantiomer of the ligand can be synthesized via the second route from the appropriate enantiomer of the 1,4-diol. Asymmetric hydrogenation using catalyst precursor 36 on acetamidoacrylic acid derivatives provided modest to good enantioselectivity (77-95% ee) under low H(2) pressure (30 psi). Asymmetric hydrogenation of CI-1008 (pregabalin) precursors, 39 and 40, provided good enantioselectivities (92%) at high catalyst loading (1 mol %) and low pressure (30 psi). Enantiomeric excesses dropped sharply with catalyst loading at this pressure. Increasing the pressure of H(2) caused a significant increase in enantiomeric excess for low catalyst loading reactions. Several studies were undertaken to further investigate the enantioselectivity dependence on both pressure and catalyst loading.

Highly selective asymmetric hydrogenation using a three hindered quadrant bisphosphine rhodium catalyst.

A concise synthesis of both enantiomers of ligand 2 and rhodium complex 5 is presented. The crux of the synthesis is a chiral HPLC separation of the enantiomers of 4. Rhodium complex 5 possesses three hindered quadrants in the steric environment within which a substrate binds. Evidence is presented that this configuration leads to high enantioselectivity (>99% ee) for rhodium-catalyzed asymmetric hydrogenation of alpha-acetamido dehydroamino acids, 6a-e. High enantioselectivities are also reported for the hydrogenation of a substrate precursor, 8, of pharmaceutical candidate, pregabalin. Advantages for large-scale hydrogenation of 8 using catalyst 5a vs Rh-Me-DuPhos are discussed.

An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation.

A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.