Applications of chiral C2-symmetric vicinal diamines in asymmetric sythesis

- Jan 24, 2018 -

    Chiral C2-symmetric vicinal diamines have emerged as powerful tools for the synthesis of enantiomerically pure compounds and are now commonly used as chiral auxiliaries or ligands for a wide array of asymmetric chemical transformations, with efficiencies comparable to those obtained with the closely related 1,2-diols. (1S,2S)- 1,2-Diaminocyclohexane (also named (1S,2S)-1,2-cyclohexanediamine), together with its (1R, 2R) enantiomer, allows excellent levels of asymmetric induction in many reactions, for which it has become the ligand of choice. Its applications in asymmetric synthesis and catalysis often involves the preparation of various N,N’-substituted derivatives.


Resolving Reagent. Although (1S,2S)- 1,2-diaminocyclohexane is not a commonly used resolving reagent, it has been used for the resolution of 1,2-diols, the most important application being the resolution of 1,1-binaphthol (BINOL) and other atropoisomeric alcohols.

    Bicyclic phosphoramines derived from N,N’-dimethyl-diaminocyclohexane have been used for the determination of enantiomeric purities of chiral alcohols, amines, and thiols using spectroscopic and chromatographic techniques. The thiophosphoramide derived from 1 allows the determination of enantiomeric purity of alcohols by 31PNMR analysis via the hydroxyl adduct 2 with excellent resolution of diastereomers(eq1).


Chiral Auxiliary. Chiral 1,2-diamines have often been used as chiral auxiliaries in various carbon-carbon bond-forming reactions. The reaction of a diamine with an aldehyde gives a chiralaminal which can undergo stereoselective reactions. This was applied in the synthesis of enantiomerically pure a-hydrazino aldehydes by stereoselective addition of carbon nucleophiles onto the aminal of glyoxal monohydrazone (eqs 2 and 3).In this reaction, the use of 1,2-diaminocyclohexane gave lower diastereomeric excesses than with the related 1,2-diphenyl ethylenediamine.



 The same chiral auxiliary has also been used for the stereoselective synthesis of arene-chromium complexes: treatment of an aromatic aminal with chromium hexacarbonyl gives the corresponding complex with high diastereomeric excess. This protocol was recently applied in a total synthesis of (-)-lasubine (eq 4).


    A successful application of 1,2-diaminocyclohexane (as its 1R,2R enantiomer) as a chiral auxiliary is illustrated by the diastereoselective alkylation of the potassium enolate of bis-amide(3) with electrophiles such as benzyl bromide to give bis-alkylated products with excellent diastereoselectivity (eq 5). Lower levels of induction were obtained using related 1,2-diphenyl ethylenediamine.


  Chiral imidazolines such as 4, obtained by condensation of iminoether hydrochlorides with (1S,2S)-1,2-diaminocyclohexane, may be metalated and alkylated with high stereoselectivity. This process is highly efficient for the stereoselective synthesis of quaternary benzylic stereogenic centers, and has been applied to a total synthesis of mesembrine (eq 6). (1S,2S)-1,2-Diaminocyclohexane here again gives higher diastereomeric excesses than 1,2-diphenyl ethylenediamine in this reaction.


   The asymmetric synthesis of chiral phosphonic acids has been accomplished starting from alkyl phosphonamides 5 derived from N, N’-dimethyl-diaminocyclohexane, which are easily prepared by condensation with alkyl phosphonic dichlorides (eq 7). Upon metalation with a strong base, the corresponding anion reacts with a great variety of electrophiles with high stereoselectivity. This has been applied to conjugate addition, cyclopropanation, α-amination, and enantioselective Wittig reactions (eq 8).



Chiral Reagent. The diamino phenyl borane (6) derived from (1S,2S)-1,2-diaminocyclohexane has been used as a chiral proton source for the enantioselective protonation of prochiral cyclic lithium enolates, with ee's up to 93% (eq 9). (1S,2S)-1,2-Diaminocyclohexane proved to be highly superior to 1,2-diphenyl ethylenediamine or bis-naphthylamine.


Chiral Ligand for Asymmetric Catalysis. (1S,2S)- 1,2-Diaminocyclohexane and its derivatives are among the most frequently used chiral ligands for a variety of catalytic asymmetric transformations. N,N’-disubstitution allows fine tuning of steric and electronic properties of each ligand, using either electronwithdrawing or electron-donating substituents. The main derivatives are bis-alkyl, bis-acyl, bis-sulfonyl, and bis-imino compounds.


(1S,2S)-1,2-Diaminocyclohexane. (1S,2S)- 1,2-Diaminocyclohexane along with other chiral 1,2-diamines has been used as ligand for the ruthenium-catalyzed hydrogenation of ketones. Chiral bisphosphine-ruthenium(II) diamine complexes have shown high efficiency in the catalytic hydrogen transfer from isopropanol to aromatic and conjugated ketones (eq 10). Complexes including (1S,2S) 1,2-diaminocyclohexane gave slightly lower ee's than those with 1,2-diphenyl ethylenediamine or 1,1-dianisyl-2-isosopropyl-l,2-ethylenediamine (DAIPEN). The enantioselective reduction of ketones may also be performed with polyhydroxysilane in the presence of a zinc diamine complex. Using (1S,2S)-1,2-diaminocyclohexane or its alkylated derivatives, ee's were lower than with other chiral diamines.

equation 10.jpg

   Another application of the free diamine as a ligand for asymmetric catalysis is the Michael reaction of cyclic p-keto esters with methyl vinyl ketone, which has been accomplished with a nickel(II)- (1S,2S)- 1,2-diaminocyclohexane complex, with ee's up to 91% (eq 11).

equation 11.jpg