Modular asymmetric synthesis of P-chirogenic beta-amino phosphine boranes

A short concise route to beta-aminophosphine boranes is presented via the desymmetrization of prochiral phosphine boranes, forming P-chirogenic aldehydes that are rapidly transformed to the target compounds employing reductive amination under microwave irradiation. This sequence provides a modular route to P-chirogenic P,N ligands, and in addition, the intermediate aldehydes are versatile P-chiral building blocks for ligand design in general. An alternative pathway via the corresponding alpha-carboxyphosphines is also described. The ligands were subsequently evalutated in the asymmetric conjugate addition of diethylzinc to trans-beta-nitrostyrene.     

Highly enantiomerically enriched alpha-haloalkyl Grignard reagents

alpha-Chloro- and alpha-bromoalkyl Grignard reagents 11 and 30 with > 97% ee (enantiomeric excess) were generated by a sulfoxide/magnesium exchange reaction from the enantiomerically and diastereomerically pure sulfoxides 25 and 27. The resulting alpha-haloalkyl Grignard reagents are configurationally stable at -78 degrees C. Racemization sets in at or above -60 degrees C, especially when the solution contains bromide ions. In the absence of halide ions, the configurational stability extends up to -20 degrees C, when chemical decomposition commences.     

Highly efficient synthesis of enantiomerically enriched 2-hydroxymethylaziridines by enzymatic desymmetrization

Both enantiomers of protected and unprotected 2-hydroxymethylaziridines are efficiently and enantiospecifically synthesized by using a combination of enzymatic and synthetic methods. PPL was used for lipase-catalyzed desymmetrization of N-protected serinol. [reaction: see text].     

Chemoenzymatic synthesis of enantiomerically enriched kavalactones

Lipase-mediated kinetic resolution of methyl-3-hydroxy-5-phenylpentanoate and (6E)-ethyl 5-hydroxy-3-oxo-7-phenylhept-6-enoate is described in high enantiomeric excess and good yields. The effect of different lipases in different solvents has been screened using different acylating agents. This protocol has been extended for the preparation of enantiomerically pure biologically important kavalactones.     

Highly stereoselective synthesis of tertiary propargylic centers and their isomerization to enantiomerically enriched allenes

Center of attention: A new approach for the synthesis of enantiomerically enriched allenes by isomerization of 2-p-tolylsulfinylphenyl propargylic derivatives is presented, which in turn are prepared by reaction of sulfinylated lithium benzylcarbanions with arylsulfonylacetylenes. The high control of stereoselectivity in both steps is exerted by the sulfinyl group.     

Chemoenzymatic synthesis of enantiomerically enriched aminoalkenols and glycosides thereof

1-t-Butoxycarbonylamido-3-pentene-1-ol 3 and 2-azido-4-phenyl-3-butene-1-ol 4 were enantiomerically enriched by enzymatic acetylation using various lipases and esterases (CHIRAZYM) to give acetylated compounds 5 and 7, respectively. Compound 3 gave the best results (E=94) with Candida antarctica A lipase (CHIRAZYM L-5), whereas 4 could not be separated into the enantiomers with satisfactory E values. The absolute configurations were proven for both compounds via independently prepared derivatives. Both enantiomers of 5, as well as racemic 7, were N-deblocked and condensed with octonic acid derivatives 14 to give the corresponding C-glycosides 17 and 22 after deprotection of the intermediates in good overall yield. Compound 4 was similarly condensed with glucose imidate 11 to give the diastereomeric O-glycosides 13 after deprotection. The latter glycosides were prepared as precursors for the generation of the corresponding aldehydes as substrates for aldolase catalyzed reactions.     

Organocerium additions to proline-derived hydrazones: synthesis of enantiomerically enriched amines

The addition of organocerium reagents (from both organolithium and organomagnesium precursors) to chiral aldehyde hydrazones prepared from 1-aminoproline derivatives has been studied. The additions proceed in good yield and high diastereoselectivity and with good nucleophile (Me, n-Bu, i-Pr, t-Bu, Ph, etc.) and substrate scope (alkyl, alkenyl and aryl). The resulting hydrazines can be converted to amines by N–N bond cleavage through hydrogenolysis (Raney nickel) or by acylation and cleavage with Li/NH₃. The influence of the side chain on the diastereoselectivity was investigated through variation of the substituents to include more coordinating atoms (oxygen and nitrogen) as well as the removal of coordinating atoms. The SAMEMP auxiliary bearing a 2-methoxyethoxymethyl group gave the highest diastereoselectivities. Remarkably, auxiliaries bearing simple methyl and isobutyl substituents gave high selectivities as well. Hypotheses for the origin of the selectivity are presented.     

Nitrile biotransformations for the synthesis of enantiomerically enriched Baylis-Hillman adducts

Catalysed by the nitrile hydratase/amidase-containing Rhodococcus sp. AJ270 cells, a number of beta-aryl- and beta-alkyl- beta-hydroxy-alpha-methylenepropiononitriles (the Baylis-Hillman nitriles) 1 underwent hydrolysis under mild conditions to produce the corresponding enantiomerically enriched Baylis-Hillman amides 2 and acids 3. The enantioselectivity of the biotransformations was strongly determined by the steric effect of the substituents at the beta-position of the substrates. The protection of the free hydroxy of beta-phenyl-beta-hydroxy-alpha-methylenepropiononitrile 1a by methylation led to the enhancement of enantiocontrol of the biohydrolysis.     

Synthesis of enantiomerically enriched amino sulfide building blocks from acyclic chiral amino allylsilanes

An efficient synthesis of various protected syn-β-sulfenyl amides is described. These are prepared from the corresponding enantiopure amino allylsilanes which are in turn obtained from naturally occurring amino acids. The key step for introduction of the sulfur substituent is a diastereoselective electrophilic sulfodesilylation which is carried out with phthalimidesulfenyl chloride. The resulting homochiral β-phthalimidesulfenyl amines with an allylic sulforated stereogenic center are useful building blocks, as they represent a starting point for subsequent functional manipulations.     

Oxiranyl anion-mediated synthesis of highly enantiomerically enriched styrene oxide derivatives

[reaction: see text] The stereospecific alpha-lithiation of optically active styrene oxides and the trapping reaction of the corresponding highly reactive intermediates with electrophiles to produce optically active styrene oxide derivatives are described. This methodology has been applied to the synthesis of an optically active oral antifungal agent of industrial interest.     

A convenient method for synthesis of enantiomerically enriched methylphenidate from N-methoxycarbonylpiperidine

[formula: see text] This report describes a new method to prepare optically active methylphenidate starting from piperidine. The method consists of a transformation of N-methoxycarbonylpiperidine to the corresponding alpha-methoxylated carbamate I by utilizing electrochemical oxidation followed by the coupling reaction with optically active Evans imides II to produce optically active methylphenidate derivatives III with high stereoselectivities, threo-(2R,2'R)-Methylphenidate (IV; Ar = Ph; Ritalin) was easily prepared from III in three steps.     

Highly functionalized organolithium reagents for enantiomerically pure alpha-amino acid synthesis

[reaction: see text] Highly functionalized l-serine-derived organolithium reagents have been generated and reacted with a variety of electrophiles, delivering novel enantiomerically pure adducts. These adducts were then converted into homochiral amino alcohols and novel nonproteinogenic alpha-amino acids, including an aspartic acid mimic that has been synthesized in an enantiomerically pure form for the first time.     

Intramolecular alkene carboamination reactions for the synthesis of enantiomerically enriched tropane derivatives

The synthesis of tropane derivatives via intramolecular Pd-catalyzed alkene difunctionalization reactions is described. Enantiopure N-aryl-γ-aminoalkenes bearing an aryl or alkenyl halide adjacent to the amino group were converted to benzo- or cycloalkenyl-fused tropane products in good yield and with no loss of enantiopurity.     

Asymmetric synthesis of highly substituted beta-nitro alcohols and enantiomerically enriched 4,4,5-trisubstituted oxazolidinones

It is demonstrated that alpha,alpha-disubstituted-alpha-nitroketones are reduced to the corresponding trisubstituted nitro alcohols in good to excellent yield and enantiomeric excess by borane-dimethyl sulfide in the presence of a chiral oxazaborolidine catalyst. Reduction of the nitro alcohols to the corresponding amino alcohols and their subsequent conversion to enantiomerically enriched 4,4,5-trisubstituted oxazoldinones is also reported.     

A new chemoenzymatic Baylis-Hillman approach for the synthesis of enantiomerically enriched umbelactones

An efficient and convenient strategy for the enantioselective synthesis of enantiomerically enriched umbelactones is described utilizing a lipase-mediated resolution protocol, Baylis-Hillman reaction and ring closing metathesis as key steps. The lipase-resolution is carried out using several lipases from various sources in different solvents to afford the required intermediate 8 in good yield and high enantioselectivity.     

Chemoenzymatic synthesis of highly enantiomerically enriched secondary alcohols with a thiazolic core

Stereoselective preparative enzymatic acylation and hydrolysis/methanolysis of various C-substituted rac-thiazol-2-yl-methanols were achieved for the preparation of enantiopure or enantiomerically enriched, naturally occurring 2-hydroxymethylthiazoles. The absolute configurations of the resulting secondary alcohols were determined by a detailed ¹H NMR study of Mosher’s derivatives.     

Enantiomerically enriched cyclopropene derivatives: versatile building blocks in asymmetric synthesis

Enantiomerically enriched cyclopropene derivatives, the smallest possible unsaturated carbocycles, are of great synthetic interest since they serve as versatile reactive building blocks. Their reactivity results from the relief of the ring strain in the small molecule. They can be transformed into a wide variety of complex chiral structures and a special emphasis will be directed towards the preparation of enantiomerically enriched methylene- and alkylidenecyclopropane derivatives. The ready availability of a wide range of these chiral entities now provides an excellent opportunity to discover new and unique transformations that can further enrich mainstream synthetic methodology.     

One-pot synthesis of enantiomerically enriched 2,3-disubstituted cyclopentanones via copper-catalyzed 1,4-reduction and alkylation

[reaction: see text]. Enantiomerically enriched 2,3-disubstituted cyclopentanones were prepared via copper-catalyzed 1,4-reduction of 3-substituted cyclopentenones followed by alkylation of the resulting silyl enol ether. Using this procedure, trans-2,3-disubstituted cyclopentanones were produced in moderate to good overall yields (42-67%) and with excellent enantiomeric and diastereomeric excesses. The reduction and alkylation were performed in a single reaction vessel.