Synthesis of chiral norbornane derivatives as γ-amino alcohol catalysts: the effect of the functional group positions on the chirality transfer

Starting from (1S,4R) chiral ketone (+)-6, we developed a synthetic route to the synthesis of new chiral γ-amino alcohols (+)- and (−)-syn-2-amino-7-hydroxy norbornane derivatives with excellent yields and enantiomeric excesses (up to 99%). These compounds were tested as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde presenting moderate results. The results obtained, compared with others previously reported, showed that the relative disposition of the amino and hydroxyl groups on C(2) and C(7) positions, play an important role in the catalytic activity.     

(S)-(−)-α-Methylbenzylamine as an efficient chiral auxiliary in enantiodivergent synthesis of both enantiomers of N-acetylcalycotomine

(S)-(−)-α-Methylbenzylamine 2 was used as a chiral auxiliary in the enantiodivergent synthesis of simple isoquinoline alkaloids. The prochiral imine moiety in compound 4 was reduced with different reagents, giving diastereomeric amines 5a or 5b, which subsequently were transformed to either (S)-(−)-N-acetylcalycotomine 6 or (R)-(+)-N-acetylcalycotomine ent-6 in good enantiomeric excess. ¹⁹F NMR of its Mosher's acid ester was used to establish the purities of final compounds.     

2-Methoxy-2-(1-naphthyl)propionic acid,a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1H NMR anisotropy method

Racemic 2-methoxy-2-(1-naphthyl)propionic acid (1, MαNP acid) was enantioresolved as its esters derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (±)-1 and (1R,3R,4S)-(−)-menthol was easily separated by HPLC on silica gel yielding esters (−)-2a and (−)-2b, the separation factor α=1.83 being unusually large. The ¹H NMR chemical shift differences, Δδ=δ(R)–δ(S), between diastereomers 2a and 2b, are much larger than those of conventional chiral auxiliaries, e.g. Mosher’s MTPA and Trost’s MPA acids. This acid 1 is therefore very powerful for determining the absolute configuration of chiral alcohols by the ¹H NMR anisotropy method. Solvolysis of the separated esters yielded enantiopure acids (S)-(+)-1 and (R)-(−)-1, which are useful for enantioresolution of racemic alcohols.     

Further enantioselective syntheses of α-arylalkanamines via intermediate addition of Grignard reagents to a chiral hydrazone derived from (R)-(−)-2-aminobutan-1-ol

Reaction of various aromatic aldehydes with the chiral hydrazine (R)-(−)-2, derived from 2-aminobutan-1-ol (R)-(−)-1, gave the corresponding hydrazones 5–12. Enantioselective addition of EtMgBr or n-BuMgBr to 5–8 gave the trisubstituted hydrazines 13a–f (d.e.s=100%). Catalytic hydrogenolysis (6 bar/Pd–C/110°C/5 h) of the N–N bond of the latter afforded the enantiomerically enriched α-arylalkanamines (R)-(+)-14a–f (e.e.s=90–93%).     

A straightforward synthesis of both enantiomers of allo-norcoronamic acids and allo-coronamic acids,by asymmetric Strecker reaction from alkylcyclopropanone acetals

Methylcyclopropanone hemiacetal (2S)-3a underwent the asymmetric Strecker reaction induced by a chiral amine to provide a useful synthesis of enantiomerically pure (1R,2S)-(+)-allo-norcoronamic acid 1 in good yield and high enantiomeric excess. From racemic alkyl hemiacetal (±)-3, the same methodology also constituted a useful way to prepare both (+)-1 and (−)-1 and (+)-allo-coronamic acid 2 and its antipode (−)-2 with good yield and high enantiomeric excess.     

An improved synthesis of enantiomerically pure CIP-AS,a potent and selective AMPA-kainate receptor agonist

CIP-AS (−)-2, a chiral amino acid structurally related to glutamic acid, behaves as a potent agonist at the ionotropic AMPA-kainate receptors and was previously prepared in low overall yield through the 1,3-dipolar cycloaddition of ethoxycarbonylformonitrile oxide to N-BOC-3,4-didehydro-(S)-proline methyl ester (−)-6. Herein, we report an alternative strategy based on the cycloaddition of the same dipolarophile to N-(4-methoxybenzyl)-α-ethoxycarbonylnitrone 12. The mixture of stereoisomeric 3-ethoxycarbonyl-N-(4-methoxybenzyl)isoxazolidinyl prolines 13 was then converted into the corresponding 3-ethoxycarbonyl-Δ²-isoxazolinyl prolines by DDQ mediated oxidation. The new strategy yielded the precursor of CIP-AS in satisfactory overall yield and represents an improvement upon the existing procedure in terms of yield and efficiency.     

Synthesis of enantiopure 1,1′-(1-dimethylamino-propanediyl)ferrocene via a highly diastereoselective imine reduction

1,1′-(1-Oxo-propanediyl)ferrocene 4 reacts with (S)-(−)-1-(1-naphthylethyl)amine to give the corresponding syn imine exclusively which undergoes a highly diastereoselective reduction with sodium borohydride to give the diastereomerically pure (R,S)-(+)-amine 6. Conversion of 6 leads in three steps to the final product (R)-(+)-1,1′-(1-dimethylamino-propanediyl)ferrocene 2 in 53% overall yield (based on 4) and in >98% e.e. Use of (S)-(−)-1-phenylethylamine as the chiral auxiliary leads to an 84:16 mixture of syn and anti imines. After reduction and separation of the resulting diastereomers the major isomer (R,S)-(−)-10 can also be converted to the final product (R)-(+)-2 in 55% overall yield (based on 4) and in >98% e.e.     

Preparation and resolution of 2,2′-dimercapto-6,6′-dimethoxy-1,1′-biphenyl: a C2-symmetric sulfur building block

The preparation of the title dimercaptan 1 starting from 2,2′-dihydroxy-6,6′-dimethoxy-1,1′-biphenyl 2 is described. Resolution of dimercaptan 1 was performed using (−)-(1R,2S,5R)-menthyl chloroformate as a chiral resolving agent. The procedure affords dimercaptan (+)-1 and (−)-1 in 98% ee and 93% ee, respectively. A new and direct intermolecular Ullmann coupling resulting in an improved preparation of diol 2 is also reported.     

Resolution of 7-oxabicyclo[2.2.1]hept-5-en-2-one via cyclic aminals

High yielding resolution of racemic 7-oxabicyclo[2.2.1]hept-5-en-2-one (±)-1 (`7-oxanorbornenone') via aminal formation with (R,R)-1,2-diphenylethylenediamine 2 is reported. Acidic hydrolysis furnishes the enantiomeric ketones (+)-1 and (−)-1 (≥95% ee). The chiral diamine is efficiently recovered.     

Synthesis of versatile chiral intermediates by enantioselective conjugate addition of alkenyl Grignard reagents to enamides deriving from (R)-(−)- or (S)-(+)-2-aminobutan-1-ol

Conjugate addition of but-3-enylmagnesium bromide to the chiral crotonamide (R)-(+)- and (S)-(−)-3, followed by hydrolysis and oxidation, afforded enantiopure (R)-(+)- and (S)-(−)-3-methyladipic acids 8, respectively. Conjugate addition of vinylmagnesium chloride to the chiral crotonamide and cinnamamides (R)-(+)-3–5, followed by hydrolysis, gave the alkenoic acids (S)-12–14, respectively. Iodolactonization of the latter led to the 5-iodomethyllactones (+)-15–17, which were reduced by means of n-Bu₃SnH into the trans-disubstituted 5-methyllactones (+)-19–21, respectively. Treatment of the iodomethyllactone (+)-16 with LiMe₂Cu or n-Bu₂CuLi furnished the trans-5-alkyl-4-phenyllactones (−)-22 or (+)-23.     

Enzyme-mediated preparation of enantioenriched forms of trans- and cis-p-menthan-1,8-dien-5-ol

The synthesis of the trans-p-menthan-5-ol (±)-1 was carried out by Diels–Alder cycloaddition of 3-keto-1-butenyl-acetate 3 with isoprene followed by Wittig methylenation. PS lipase resolution of the alcohol afforded acetate (−)-5 with 98% ee, which was hydrolysed to give (−)-1. Alternatively, enzymatic hydrolysis of a keto ester followed by Wittig methylenation and hydrolysis afforded the same alcohol with an ee of 86%. The cis-p-menthan-5-ol (−)-2 was obtained by Swern oxidation of (−)-1, followed by diastereoselective reduction with L-Selectride without lost of enantiomeric excess.     

Synthesis of (S)-(−)- and (R)-(+)-O-methylbharatamine using a diastereoselective Pomeranz–Fritsch–Bobbitt methodology

Laterally lithiated (S)-(−)- and (R)-(+)-o-toluamides 6 with a chiral auxiliary derived from (S)- and (R)-phenylalaninol, respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz–Fritsch–Bobbitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)-7 and (−)-7 along with acyclic products, (−)-8 and (+)-8, respectively. LAH-reduction of (+)-7 and (−)-7, followed by cyclization, afforded both enantiomers of the alkaloid, (S)-(−)- and (R)-(+)-O-methylbharatamine 5, in 32% and 40% overall yield and with 88% and 73% ees, respectively.     

Enzymes in organic chemistry. Part 10: Chemo-enzymatic synthesis of l-phosphaserine and l-phosphaisoserine and enantioseparation of amino-hydroxyethylphosphonic acids by non-aqueous capillary electrophoresis with quinine carbamate as chiral ion pair agent

Diisopropyl 2-azido-1-acetoxyethylphosphonate (±)-7 was hydrolysed with high enantioselectivity by lipase SP 524 to give α-hydroxyphosphonate (S)-(−)-6 and ester (R)-(−)-7, which was saponified to give (R)-(+)-6. The two α-hydroxyphosphonates (R)- and (S)-6 were transformed into l-phosphaisoserine and l-phosphaserine, respectively. Their enantiomeric excesses were determined to be 97% by HPLC on an chiral stationary phase. A mixture of all four stereoisomeric amino-hydroxyethylphosphonic acids can be separated by non-aqueous capillary electrophoresis with quinine carbamate as the chiral ion pair agent applying the partial filling technique.     

Improved synthetic methods of CP-060S,a novel cardioprotective drug

Two synthetic methods of CP-060S, (−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-[3,4-(methylenedioxy)phenoxy]ethyl]amino]propyl]-1,3-thiazolidin-4-one (−)-1, have been developed. The first method involved preparative HPLC resolution of bromo-intermediate 4. The second one involved resolution of 1 by crystallization of the corresponding diastereomeric salt.     

The cleavage of meso-epoxides with homochiral thiols: synthesis of (+)- and (−)-trans-1-mercaptocyclohexan-2-ol

The synthesis of (+)- and (−)-trans-1-mercaptocyclohexan-2-ol is described. Ring opening of cyclohexene oxide with (−)-4-methoxybenzylnopan-3(R)-thiol 1a followed by oxidation gives two readily separable diastereomeric sulfoxides. These sulfoxides display very different thermal stability but both undergo regio-specific syn-elimination to give cyclohexan-1-ol-2-sulfenic acid that can be reacted in situ with 3,5-dimethylthiophenol to give a mixed disulfide. Reduction of these disulfides with lithium aluminium hydride gives the title compounds in enantiomerically pure form.     

First stereoselective synthesis of (4aS,5R)-4,4a,5,6,7,8-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone

The synthesis of enantiomerically pure (4aS,5R)-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone (−)-1 is described for the first time. The synthesis starts from (R)-3-methylcyclohexanone and involves the preparation of Piers enol lactone 6 in its enantiopure form as the key intermediate. Treatment of (+)-6 with methyl lithium followed by an intramolecular aldol reaction gives the bicyclic enone (−)-1.     

Stereoselective syntheses and transformations of chiral 1,3-aminoalcohols and 1,3-diols derived from nopinone

A library of 1,3-difunctionalized pinane derivatives were synthesized and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. 1,3-Aminoalcohol 6a was prepared from (−)-nopinone 2 via stereoselective Mannich condensation and reduction of the resulting β-amino ketone 4. The key aminoalcohol 6a was transformed into primary, secondary and tertiary substituted aminoalcohols in order to study the effect of the substituent on catalytic activity. Starting from (−)-nopinone, cis- and trans-β-hydroxy esters 15 and 16 were prepared in a two-step stereoselective synthesis. Reduction of the hydroxy esters resulted in pinane-based 1,3-diols, while hydrolysis of the esters, followed by DCC-mediated amidation and subsequent reduction, led to cis- and trans-N-benzyl-1,3-aminoalcohols 8 and 23. trans-N-Benzyl-1,3-aminoalcohol 8 was also prepared by selective mono-debenzylation of 6a via a continuous-flow process in an H-Cube® system. The resulting aminoalcohols and diols were applied as chiral catalysts in the reaction of diethylzinc and benzaldehyde.     

Diastereoselective Pomeranz–Fritsch–Bobbitt synthesis of (S)-(−)-salsolidine using (R)-N-tert-butanesulfinylimine as a substrate

The highly diastereoselective addition of methyl Grignard reagent to chiral (R)-N-tert-butanesulfinylimine 8 was the key step in the synthesis of (S)-(−)-salsolidine 1 of high enantiomeric purity. The resulting addition product, tert-butanesulfinylamide 9, was then subjected to cyclization via amine 10 and Pomeranz–Fritsch aminoacetal 11.     

Preparation of chiral α-diazophosphonic acid derivatives

The chiral α-diazophosphonic acid derivatives 3, 6 and 8 were prepared from (−)-ephedrine and (S,S)-N,N′-dimethyl-1,2-diaminocyclohexane; preliminary experiments suggest that the chiral auxiliary exerts little influence in the dirhodium(II) acetate catalysed OH and NH insertion reactions.     

Influence of Lewis acids on the [4+2] cycloaddition of (2R,2′R)-N,N′-fumaroylbis[fenchane-8,2-sultam] to cyclopentadiene and cyclohexadiene

Compared to the analogous bornane-10,2-sultam derived dienophile (−)-1b, the reversed topology observed during the [4+2] cycloaddition of cyclopentadiene or cyclohexadiene to the (−)-1a–TiCl₄ chelate can be rationalised on the basis of IR studies of their complexes with different Lewis acids. According to X-ray analyses, the origin of this differentiation resides in the loss of masked C₂ symmetry, due to the pseudoequatorial ‘down’ orientation of the SO(1) bond in (−)-1a,c as compared to the pseudoequatorial ‘up’ direction adopted by the SO(2) bond in (−)-1b,d, associated with the steric influence of the apical Ti–Cl atoms. Dependent on the strength of the Lewis acid, the much higher constraint of the SO₂/CO syn-s-cis conformer diminishes the chelating properties of this type of fenchane-8,2-sultam derived dienophiles (−)-1a and 1c.