A scalable synthesis of (R)-3-(2-aminopropyl)-7-benzyloxyindole via resolution

(±)-3-(2-Aminopropyl)-7-benzyloxyindole 1, assembled from 7-benzyloxyindole 3 in 59% overall yield, is resolved with O,O′-di-p-toluoyl l-(2R,3R)-tartaric acid 7 into (R)-1, a key intermediate of AJ-9677 2 (selective adrenaline β₃-agonist) in 99.5% e.e. and 36% overall yield. The unwanted enantiomer (S)-1 (61.9% e.e.; recovered in 57% yield from the crystallization filtrate) can be reused in another round of resolution after its enantiomeric purity is lowered to 3.7% by Raney Co treatment under a hydrogen atmosphere.     

Resolution of 1-n-propoxy-3-methyl-3-phospholene 1-oxide by diastereomeric complex formation using TADDOL derivatives and calcium salts of O,O′-dibenzoyl-(2R,3R)- or O,O′-di-p-toluoyl-(2R,3R)-tartaric acid

1-n-Propoxy-3-methyl-3-phospholene 1-oxide was prepared in optically active form by extending resolution methods applying (−)-(4R,5R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane (‘TADDOL’) and (−)-(2R,3R)-α,α,α′,α′-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol (‘spiro-TADDOL’), as well as the acidic and neutral Ca²⁺ salts of (−)-O,O′-dibenzoyl- and (−)-O,O′-di-p-toluoyl-(2R,3R)-tartaric acid. In one case, the diastereomeric complex could be identified by single crystal X-ray analysis. The absolute P-configuration of the enantiomers of the phospholene oxide was also determined by CD spectroscopy.     

Studies on two different diastereoselective reaction pathways from a serinol derivative to 4-hydroxymethyl-2-oxazolidinones using 2-chloroethyl chloroformate and N,N′-disuccinimidyl carbonate

Two reaction pathways and their diastereoselectivity-determining steps of the asymmetric desymmetrization of (R)-2-(α-methylbenzyl)amino-1,3-propanediol 1 with 2-chloroethyl chloroformate (CCF) and with N,N′-disuccinimidyl carbonate giving (4S,αR)-4-hydroxymethyl-3-α-methylbenzyl-2-oxazolidinones (4S)-3 and its (4R,αR)-diastereomer (4R)-3 were investigated. The reaction of serinol 1 and CCF to give the corresponding carbonates was not a diastereoselectivity-determining step. The carbonates gave (R)-5-(α-methylbenzyl)amino-1,3-dioxan-2-one 4 after addition of DBU, and an intramolecular acyl transfer of 4 was found to be a diastereoselectivity-determining step to give (4S)-3. Conversely, the reaction of serinol 1 and N,N′-disuccinimidyl carbonate afforded directly the opposite diastereomer (4R)-3 but not via the intermediate 4. Thus, their diastereoselectivities depended on the acylating reagent.     

Asymmetric Diels–Alder reaction using a new chiral β-nitroacrylate for enantiopure trans-β-norbornane amino acid preparation

The main nitronorbornene adduct derived from the asymmetric Diels–Alder reaction of (S)-benzyl-4-(3-(3-nitroacryloyloxy)-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (S)-1 and cyclopentadiene was isolated and transformed to afford the enantiopure bicyclic β-amino acid (1S,2R,3R,4R)-trans-β-norbornane amino acid 9. The enantiomer (1R,2S,3S,4S)-9 could be obtained by the same synthetic route by using the chiral auxiliary (R)-1.     

Efficient synthesis of 3,4- and 4,5-dihydroxy-2-amino-cyclohexanecarboxylic acid enantiomers

An efficient method for the synthesis of (1S,2R,4R,5S)- and (1R,2R,4R,5S)-2-amino-4,5-dihydroxycyclohexanecarboxylic acids (?)-6 and (?)-9 and (1R,2R,3S,4R)- and (1S,2R,3S,4R)-2-amino-3,4-dihydroxycyclohexanecarboxylic acids (?)-15 and (?)-18 was developed by using the OsO₄-catalyzed oxidation of Boc-protected (1S,2R)-2-aminocyclohex-4-enecarboxylic acid (+)-2 and (1R,2S)-2-aminocyclohex-3-enecarboxylic acid (+)-11. Good yields were obtained. The stereochemistry of the synthesized compounds was proven by NMR spectroscopy.     

An efficient large scale resolution of (±)-threo-methylphenidate hydrochloride (Ritalin® hydrochloride)

An efficient and large scale preparation of (2R,2′R)-(+)-threo-methylphenidate hydrochloride (3) by the resolution of (±)-threo-methylphenidate hydrochloride (1) salt with O,O′-dibenzoyl-d-(+)-tartaric acid in the presence of 4-methylmorpholine is described.     

Resolution of inherently chiral anti-O,O′-dialkylated calix[4]arenes and determination of their absolute stereochemistries by CD and X-ray methods

Inherently chiral anti-O,O′-dibenzyl-p-tert-butylcalix[4]arene 1 was resolved as the (S)-2-methoxy-2-(naphthalen-1-yl)propionic ester by flash chromatography. Conversely, the anti-O,O′-dibutyl analogue 2 was resolved as the (S_a)-2′-methoxy-1,1′-binaphthalene-2-carboxylic ester by crystallization combined with flash chromatography. CD analysis of these compounds indicated the absolute stereochemistries to be (S_a)-(+)-1 and (S_a)-(+)-2, respectively, the former of which was confirmed by X-ray crystallographic analysis.     

Synthesis of mono- and dihydroxy-substituted 2-aminocyclooctanecarboxylic acid enantiomers

(1R,2S,6R)-2-Amino-6-hydroxycyclooctanecarboxylic acid (?)-10 was synthesized from (1R,2S)-2-aminocyclooct-5-enecarboxylic acid (+)-2 via an iodolactone intermediate, while (1R,2S,3R,4S)-2-amino-5,6-dihydroxycyclooctanecarboxylic acid (?)-12 was prepared by using the OsO₄-catalyzed oxidation of Boc-protected amino ester (?)-5. The stereochemistry and relative configurations of the synthesized compounds were determined by 1D and 2D NMR spectroscopy (based on 2D NOE cross-peaks and ³J(H,H) coupling constants) and X-ray crystallography.     

Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)-2 was prepared by the stereoselective Grignard reaction of 1-naphthylmagnesium bromide with (1R,3R,4S)-menthyl pyruvate 3 or (1R,3R,4S)-8-phenylmenthyl pyruvate 4, and the absolute configuration of acid (+)-2 was unambiguously determined to be S by the ¹H NMR anisotropy method.     

Polyhydroxylated pyrrolidines: synthesis from d-fructose of new tri-orthogonally protected 2,5-dideoxy-2,5-iminohexitols

The readily available 3-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (2) was transformed into its 5-O- (3) and 4-O-benzoyl (4) derivative. Compound 4 was straightforwardly transformed into 5-azido-4-O-benzoyl-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (7) via the corresponding 5-deoxy-5-iodo-α-l-sorbopyranose derivative 6. Cleavage of the acetonide in 7 to give 8, followed by regioselective 1-O-silylation to 9 and subsequent catalytic hydrogenation gave a mixture of (2S,3R,4R,5R)- (10) and (2R,3R,4R,5R)-4-benzoyloxy-3-benzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (12) that was resolved after chemoselective N-protection as their Cbz derivatives 11 and 1a, respectively. Stereochemistry of 11 and 1a could be determined after total deprotection of 11 to the well known DGDP (13). Compound 2 was similarly transformed into the tri-orthogonally protected DGDP derivative 18.     

Pheromone synthesis. Part 245: Synthesis and chromatographic analysis of the four stereoisomers of 4,8-dimethyldecanal, the male aggregation pheromone of the red flour beetle, Tribolium castaneum

All four stereoisomers of 4,8-dimethyldecanal (1) were synthesized from the enantiomers of 2-methyl-1-butanol and citronellal. Enantioselective GC analysis enabled separation of (4R,8R)-1 and (4R,8S)-1 from a mixture of (4S,8R)-1 and (4S,8S)-1, when octakis-(2,3-di-O-methoxymethyl-6-O-tert-butyldimethylsilyl)-γ-cyclodextrin was employed as a chiral stationary phase. Complete separation of the four stereoisomers of 1 on reversed-phase HPLC at −54 °C was achieved after oxidation of 1 to the corresponding carboxylic acid 12 followed by its derivatization with (1R,2R)-2-(2,3-anthracenedicarboximido)cyclohexanol, and the natural 1 was found to be a mixture of all the four stereoisomers.     

Polyhydroxylated pyrrolidines, III. Synthesis of new protected 2,5-dideoxy-2,5-iminohexitols from d-fructose

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (6) was straightforwardly transformed into 5-azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (8), after treatment under modified Garegg's conditions followed by reaction of the resulting 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-l-sorbopyranose (7) with lithium azide in DMF. O-debenzoylation at C(3) in 8, followed by oxidation and reduction caused the inversion of the configuration to afford the corresponding β-d-psicopyranose derivative 11 that was transformed into the related 3,4-di-O-benzyl derivative 12. Cleavage of the acetonide of 12 to give 13 followed by O-tert-butyldiphenylsilylation afforded a resolvable mixture of 14 and 15. Compound 14 was transformed into (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-dibenzyloxy-2′,5′-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (18) either by a tandem Staudinger/intramolecular aza-Wittig process and reduction of the resulting intermediate Δ²-pyrroline (16), or only into 18 by a high stereoselective catalytic hydrogenation. When 15 was subjected to the same protocol, (2S,3S,4R,5R)- (21) and (2R,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22) were obtained, respectively.     

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.     

(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in the enantioselective preparation of α-aryloxypropanoic acid herbicides and α-chlorocarboxylic acids

rac-α-Chlorocarboxylic acids, rac-9a–e, were formally deracemized by reaction of the corresponding acyl chlorides with the chiral auxiliaries (R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, (R)- and (S)-4, followed by mild alkaline hydrolysis. The highest o.p. (99%) was obtained in the case of (S)-α-chloropropanoic acid, a known precursor for the synthesis of (R)-α-aryloxypropanoic acid herbicides such as dichlorprop-P, (R)-3a, or mecoprop-P, (R)-3b, which, together with their enantiomers, were also obtained in moderate e.e.s by dynamic kinetic resolution from (αRS,3S)-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-bromopropanoate, (αRS,3S)-6, by reaction with the corresponding phenoxide followed by mild acid hydrolysis.     

A novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (−)-shikimic acid

Oseltamivir phosphate 1 was synthesized starting from a readily available acetonide, that is, ethyl (3R,4S,5R)-3,4-O-isopropylidene shikimate 2, through a new route via 11 steps and in 44% overall yield. The synthesis described in this article is characterized by two particular steps: the highly regioselective and stereoselective facile nucleophilic replacement of an OMs by an N₃ group at the C-3 position of ethyl (3R,4S,5R)-3,4-O-bismethanesulfonyl-5-O-benzoyl shikimate 5, and the mild ring-opening of an aziridine with 3-pentanol at the C-1 position of ethyl (1S,5R,6S)-7-acetyl-5-benzoyloxy-7-azabicyclo[4,1,0]hept-2-ene-3-carboxylate 8.     

Asymmetric synthesis of isoquinuclidines by Diels–Alder reaction of 1,2-dihydropyridine utilizing a chiral Lewis acid catalyst

The chiral isoquinuclidine derivative, 2-azabicyclo[2.2.2]octane ring system, endo-(7R)-3 was obtained in good yield with excellent diastereoselectivity (up to 92% de) by Diels–Alder reaction of 1-(phenoxycarbonyl)-1,2-dihydropyridine 1 with N-acryloyl-(4S)-4-benzyloxazolidin-2-one (4S)-2 using titanium-(2R,3R)-TADDOLate 4 as a chiral Lewis acid catalyst in toluene at 0 °C. On the other hand, endo-(7S)-3 was obtained in good yield with excellent diastereoselectivity (up to 97% de) by Diels–Alder reaction of 1 with (4R)-2 using Cu(OTf)₂/(4S,4′S)-bis(oxazoline) catalyst 8 as a chiral Lewis acid catalyst in dichloromethane at 0 °C. In these reactions, the choice of solvent and the combination of titanium-(2R,3R)-TADDOLate 4 {or Cu(II)/(4S,4′S)-bis(oxazoline) 8} and dienophile (4S)-2 {or (4R)-2} are very important. The stereochemistry of endo-(7R)-3 has been established to be (1R,4S,7R) and the reaction mechanism is proposed.     

Total synthesis of the 5-epimers of naturally occurring (−)-hyacinthacine A5 and unnatural (+)-hyacinthacine A4

(1R,2S,3R,5S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 10 [(+)-5-epihyacinthacine A₅] and (1R,2S,3R,5S,7aS)-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 17 [ent-5-epihyacinthacine A₄] have been synthesized by either Horner–Wadsworth–Emmons (HWE) or Wittig methodology using aldehydes 6 and 13, prepared from (2R,3S,4R,5R)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 5 (partially protected DALDP) and (2R,3S,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine 12 (partially protected DGADP), respectively, and the appropriated ylide, followed by cyclization through an internal reductive amination process of the corresponding intermediate pyrrolidinic ketones 7 and 14 and subsequent deprotection.     

Practical method for crystalline-liquid resolution of chrysanthemic acids utilizing chiral 1,1′-binaphthol monoethyl ethers directed for process chemistry

We have developed an efficient practical resolution method for (1R,3R)-trans-chrysanthemic acid 1 and (1R,3S)-trans-2,2-dimethyl-3-(2,2-dichloroethenyl)cyclopropanecarboxylic acid 2, based on the preliminary results of the simpler analogues, (1R)-2,2-dichlorocyclopropanecarboxylic acid 3 and (1R)-2,2-dimethylcyclopropanecarboxylic acid 4, using a crystalline-liquid separation procedure (without column chromatography) with chiral 1,1′-binaphthol monoethyl ethers (R)-5b as the key auxiliary. Direct esterifications of 1, 2, 3, and 4 with (R)-5b gave four sets of (1R)- and (1S)-diastereomeric esters 8, 9, 6, and 7, respectively, with markedly different melting points. All of these diastereomers were easily obtained using a simple and one-step crystalline-liquid separation. The separated diastereomers 8 and 9 were easily hydrolyzed to the desired enantiopure acids 1 (>98%) and 2 (>99%), respectively, with recovery of (R)-5b (>90%).     

Enantioselective hydrolysis of (RS)-2-fluoroarylacetonitriles using nitrilase from Arabidopsis thaliana

The enzymatic resolution of 2-fluoroarylacetonitriles (RS)-3 using nitrilase from the plant Arabidopsis thaliana is described. Racemic 2-fluoronitriles 3 are easily accessible from O-silylated aromatic cyanohydrins 2 by reaction with DAST. The nitriles (RS)-3 were hydrolysed with the nitrilase as a catalyst, not to the expected 2-fluoroarylacetic acids but to the corresponding (R)-2-fluoroarylacetamides (R)-5 as the main products. After optimization of reaction conditions (pH 9, 7°C), the enantiomeric excesses of (R)-5a,c and f (R=H, 3-Me, 3-OMe) could be improved to >99% by one recrystallization. The acid catalysed hydrolysis of (R)-5a,5c and 5f afforded the corresponding (R)-2-fluoroarylacetic acids (R)-4a,4c and 4f without racemization.     

Lipase mediated resolution of 1,3-butanediol derivatives: chiral building blocks for pheromone enantiosynthesis. Part 3

(R,S)-1,3-Butanediol 5 was kinetically resolved by enzymatic acetylation with vinyl acetate under the presence of Chirazyme™ L-2, c–f, yielding (S)-1-O-acetyl-1,3-hydroxybutane 6 and (R)-1,3-di-O-acetyl-1,3-butanediol 7 with enantiomeric excesses of 91% (E=67.3). Compounds 6 and 7 were easily transformed into the corresponding (S)-3-O-(2-methoxyethoxymethyl)-3-hydroxybutanal 10 and (R)-3-benzyloxybutanal 19, through a protection–deprotection and functional group interchange methodology. Subsequent reaction of 10 and 19 with 3-(methoxycarbonylpropionylmethylene)triphenylphosphorane afforded methyl (E,S)-8-O-(2-methoxyethoxymethyl)-4-oxo-5-nonenoate 12 and (E,R)-8-benzyloxy-4-oxo-5-nonenoate 20. The alkenes 19 and 20 were then catalytically hydrogenated to the corresponding saturated esters 13 and 21. Treatment of 13 and 21 with 1,2-ethanedithiol/F₃B·OEt₂ afforded dithioketals 14 and 22, which were respectively reduced to (S)-1,8-dihydroxy-4-nonanone ethylidenedithioketal 15 and (R)-8-O-benzyl-1,8-dihydroxy-4-nonanone ethylidenedithioketal 23. Finally, deprotection of 15 by catalytic hydrogenation under acidic conditions gave the expected (5S,7S)-(−)-7-methyl-1,6-dioxaspiro[4.5]decane 1. The (5R,7R)-(+)-1 enantiomer was analogously prepared from 23. Both compounds were formed by this procedure with an e.e. of 91%.