(1R,2S)-1-Amino-2,3-dihydro-1H-inden-2-ol1

[136030-00-7]  · C9H11NO  · (MW 149.19)

(synthetic building block used in pharmaceutical compounds, and as an asymmetric control element in chiral auxiliaries and asymmetric catalysts)

Physical Data: mp 122-124 °C.

Solubility: soluble in ethanol, isopropanol, dichloromethane, and toluene (hot).

Form Supplied in: colorless crystalline solid; commercially available in either enantiomeric form.

Analysis of Reagent Purity: NMR/CHN analysis. Chiral HPLC to confirm ee.

Preparative Methods: several routes from indene. See main text for details.

Purification: recrystallization from toluene.2d

Handling, Storage, and Precautions: relatively air- and moisture-stable, colorless, and odorless crystalline solid, irritating to skin, eyes, and respiratory system.

Preparation

A number of methods have been reported for both the racemic and asymmetric preparations of 1-amino-2,3-dihydro-1H-inden-2-ol (1), most commonly starting from inexpensive and readily available indene. These methods have been described in detail in recent reviews.1 The valuable properties of 1 as both a component of a medicinally active compound and as a chirality control element, derive primarily from its rigid and well-defined stereochemical structure. As a result, the compound is most desirable in enantiomerically pure form. One of the most efficient asymmetric syntheses of 1, which may be employed for the synthesis of either enantiomer of the target molecule, involves an asymmetric epoxidation (89% yield, 88% ee) of indene to give epoxide 2 using the well-established Jacobsen catalyst. This is followed by a Ritter reaction using oleum in acetonitrile resulting in conversion to the oxazoline (3) which is subsequently hydrolysed to the amino alcohol. Fractional crystallization with a homochiral diacid permits purification to > 99% ee (1).2

The enantioselective synthesis of 1 has also been achieved by a number of methods including enzymatic resolution of a keto ester precursor to the racemate followed by conversion of the ester to an amino group,3a enzymatic resolution of an amino azide precursor followed by reduction,4 enzymatic resolution through O-acylation of a racemic N-benzylcarbamate derivative of 1,3b and the resolution via the formation of an amide with a homochiral amino acid.5 Bioconversion of indene to trans-2S,1S-bromoindanol furnishes a key intermediate towards the synthesis of 1.6a,6b Desymmetrization of 2-TBS-protected indanol through an enantioselective oxidation provides access to a ketone precursor of 1 in up to 70% ee.6c

Application as a Synthetic Building Block in Pharmaceutical Compounds

The best-known application of the (1S,2R)-enantiomer of cis-aminoindanol is as a component of Indinavir (4), the primary component of a Crixivan® combination therapy (with other reverse transcriptase inhibitors) for AIDS.7 An excellent account of the synthetic approach to Indinavir, as well as the use of 1 in other drugs, can be found in a recent review.1a

Application as a Component of a Chiral Auxiliary

The rigid structure and well-defined conformational rigidity of 1 makes it an ideal building block for a chiral auxiliary. Three different types have been described in some detail. The ‘Evans-auxiliary’-type oxazolidinone derivative 5 has given excellent results in aldol reactions with aldehydes (2).8 The reaction illustrated, proceeding via a boron enolate, is selective for the syn diastereoisomer of product, i.e. 6, often with > 99% de. Following the reaction, the aldol product can be removed from the auxiliary using lithium hydroxide in a water/THF mixture.

The aldol reaction illustrated in 2 has been applied to the targeted synthesis of a number of complex molecules including Tylosin,8 Hapalosin,9 the antibiotic Sinefungin,10 and the HIV protease Saquinavir® inhibitor.11 Oxazolidinone-type chiral auxiliaries derived from 1 have also been employed for the control of Diels-Alder reactions of attached acryloyl or crotonyl groups.12

Asymmetric aldol reactions may also be controlled with high diasteroselectivity, but this time for the anti isomer, in reactions of N-tosyl derivatives of esters derived from 7 (3).13 Diastereoselectivities of up to 99:1 were achieved in the illustrated titanium (IV)-mediated reaction, which has been employed for the synthesis of dipeptide isosteres for incorporation into pharmaceutical building blocks.14 The selectivity reverses when a- or b- alkoxy aldehydes are employed as electrophiles.

The N-tosyl class of auxiliaries derived from 1 have also been successfully applied to the diastereocontrol of Diels-Alder reactions15,7 and the selective reduction of attached a-keto esters to furnish a-hydroxy ester products.16

A third class of chiral auxiliary derived from 1 contains a bridging isopropylidene group between the oxygen and nitrogen atoms, the removable group being appended to nitrogen. This class of auxiliary has been employed in homoaldol reactions via Zn(II) species,17 to the stereocontrol (in several cases >99% de) of [2,3]-sigmatropic rearragements18 and, in the example illustrated in 4, the asymmetric synthesis of amino acids through electrophilic amination of attached copper(I) enolates.19 a-Amino acids may also be prepared through the diastereoselective alkylation of glycine derivatives of the same auxiliary.20 Addition of organometallic reagents to a-keto amides derived from the same auxiliary provides a means for the asymmetric synthesis of a,a-disubstituted-a-hydroxy acids with excellent enantioselectivity.21

In a recent application, cis-aminoindanol has been employed as a rigid diastereocontrol element in the alkylation of bicyclic lactams and thiolactams of which they are a component.22 The resulting products form the basis of an enantioselective synthesis of alkaloids.

Application as a Component of an Asymmetric Catalyst

Amino alcohol (1) has proven to be a highly versatile ligand for use in asymmetric catalysts for a series of reactions.1 One of the most comprehensively studied uses is as an oxazaborolidine derivative such as 8 for the asymmetric control of the reduction of ketones by borane. Although its use was first described with stoichiometric levels of 1 being employed for the reduction of both ketones and oximes,3 development of the system has delivered a catalytic method requiring only 5-10 mol % catalyst.23 Enantiomeric excesses of over 85% and as high as 96% have been achieved for a range of ketone substrates. a-Chloro and a-bromo ketones are particularly excellent substrates; the reaction in 5 is the key step in a highly efficient asymmetric synthesis of the asthma drug (R,R)-formoterol24b,cand the histamine receptor antagonist Fexofenadine.24d

N,N-Dialkyl derivatives of 1 have been successfully applied to the asymmetric addition of dialkylzinc reagents to aldehydes, giving products of moderate enantiomeric excess.23 In addition, ruthenium(II) complexes of 1 have been demonstrated to be excellent catalysts for the control of the enantioselective transfer hydrogenation of ketones to alcohols at catalyst loadings as low as 1 mol %.25 The ruthenium/1 complex has been applied to a range of ketone substrates, including cyclic enones and a-amino and alkoxy substituted derivatives.

Metal complexes of bis-oxazoline derivatives (9) of 1 have been employed for the asymmetric catalysis of the Diels-Alder reactions of acryloyl-N-oxazolines with dienes. Detailed studies have been carried out into the effect of the bite angle of the ligand and the nature of the bridging group, on the efficiency of the reaction.26 In the reaction shown in 6, the copper(II) complex of the six-membered chelate ligand catalyzes the addition reaction to give a product in 94% yield and 98% ee at a loading of only 8 mol %. Use of the same ligand with magnesium(II) in place of copper(II) resulted in a reversal of the enantioselectivity, an effect which has been rationalized by a change in coordination at the metal from square planar to tetrahedral. Hetero Diels-Alder reactions have also been achieved using metal complexes of bis-oxazolines derived from 1.27 In addition, magnesium(II) complexes of the bis-oxazolines act as effective asymmetric control elements for the asymmetric conjugate [1,4] addition of free-radicals to oxazolidinone-bound cinnamates.28 Copper(I) complexes of 9 have been employed for the control of carbenoid insertions into silicon-hydrogen bonds.29

Bis-oxazoline ligands bearing a bridging 2,6-pyridine group (often referred to as ‘pybox’ ligands) have been employed for the asymmetric catalysis of alkene cyclopropanations, giving products in good enantioselectivity and diastereoselectivity at very low (0.2 mol % metal) catalyst loadings.26 However, ligands derived from certain other 1,2-amino alcohols gave superior results.

In a detailed study, bis-oxazoline (9) has been employed for the enantiocontrol of a palladium-catalyzed annulation of allenes with aryl and vinylic iodides. This procedure provided an efficient means for the asymmetric synthesis of several classes of heterocyclic target structures including indoles, cyclic ethers, and lactones.30 Bis-oxazoline (9), and certain derivatives bearing different bridging groups, have been employed in the copper-catalyzed allylic acyloxylation reaction of cyclic alkenes. Enantiomeric excesses of up to 78% were achieved using the most efficient catalyst.31

Tridentate salen ligands (10) derived from 1 have given excellent results in the enantiocontrol of the hetero Diels-Alder addition reaction of dienes with aldehydes (7)32 and in the asymmetric additions of TMS-azide to meso-epoxide33 and trimethylsilyl cyanide to benzaldehyde (up to 85% ee).34 Phosphino-oxazolines derived from 1 have been employed for the asymmetric control of palladium-catalyzed allylic substitution reactions; products of 70-90% ee were obtained.35 Photolysis of crystalline adducts of enantiomerically pure 1 with prochiral alcohols results in asymmetric inductions of up to 79% in a rare example of a solid-state enantioselective reaction.36

Related Reagents.

(1S,2R) enantiomer [26456-43-7].


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Martin Wills & Richard Eaves

Warwick University, UK



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