Chiral 1 aminoindanes

The typical technologies used for the preparation of amines have also been used for the synthesis of optically pure (R)- or (S)-l-aminoindane. For example, resolution approaches include the diastereoisomeric salt formation of racemic A-bcnzyl- l -aminoindane with (,S )-mandclic acid41 or (R,R) tartaric acid,42 which resulted in, after hydrogenation, (R)-l-aminoindane with >99% ee. Also, resolutions that use enzymatic acylation concepts have been described.43 44 The maximum theoretic yield of 50% is a clear limitation of these methods. Asymmetric synthetic approaches to chiral 1-aminoindanes have been described, including enantioselective hydrosilylation of l-indanoxime45 46 and hydroboration of indene 47 However, ee values were low to moderate. 

Merck reported the synthesis and isolation of (7 )-3,5-bistrifluoromethylphenylethanol (170) in high yields and enantiomeric excess by asymmetric hydrogen transfer. Reduction of 3,5-bistrifluoro-acetophenone (128, Ar = 3,5-(CF3)2C6H3, R = Me) with catalyst 169, prepared in situ from [RuCl2(p-cymene)]2 and (I S,2R)-cA-l-aminoindan-2-ol, produced the chiral alcohol 170 in 91-93% ee (Scheme 12.67).213... 

In this chapter, recent applications of (W)-phcnylglycine amide (1) in asymmetric synthesis are presented (Figure 25.2). The first section deals with diastereoselective Strecker reactions for the preparation of a-amino acids and derivatives, whereas the second section focuses on diastereoselective allylation of imines for preparation of enantiomerically pure homoallylamines. This latter class of compounds is a well-known intermediate for the synthesis of, for example, many types of amines, amino alcohols, and P-amino acids. The final section describes reduction of imines providing enantiomerically pure amines. (S)-3,3-Dimethyl-2-butylamine and (S)-l-aminoindane will be presented as leading examples. The results described in this chapter originate from a longstanding cooperation in the field of chiral technology development between DSM Pharma Chemicals and Syncom B.V. 

In this section, we describe as typical examples the application of (R)-PGA as a chiral vehicle in the preparation of (5)-l-aminoindane3s (see also Chapter 24) and (,S )-3,3-dimethyl-2-butylamine. (S)-l-Aminoindane is present as a key structural element (or with additional functionalization) in therapeutic agents under clinical investigation [e.g., Rasagiline mesylate, (18) for the treatment of Parkinson s disease,39 and Irindalone (19), which displays potent antihypertensive activity].40... 

Likewise, chiral templates such as (R)-phenylethylamine37 and (R)-phenylglycinol48 have been used. Use of (/ )-phenylethylamine37 provided (R)- -aminoindane from 1-indanone in 3 steps, in an overall yield of 5% and >99% ee. The low yield is caused by the nonselective removal of the chiral auxiliary in the final step. Similarly, (R)-phenylglycinol gave (5)-1-aminoindane from 1-indanone in 39% overall yield. Drawbacks in this route are the limited availability of this expensive... 

Using (S)-PGA as the chiral auxiliary would yield (R)- -aminoindane or, (R)-3,3-dimethyl-2-buty-lamine, respectively. 

Fig. 9.2.. (a) Structure of the chiral SO of Crownpak CR, the commercially available crown-ether type CSP having binaphthyl unit, and separation of the four stereoisomers of I-aminoindan-2-oI (reprinted with permission from Ref. [87]). (b) Structure of a novel crown ether type CSP with the l8-crown-6 letracarboxylic acid SO (reprinted with permis.sion from Ref. [290]). 

Davies and coworkers , for example, used iV-enoyl derivatives of a cw-l-aminoindan-2-ol based L3-oxazolidin-2-one (222) as chiral dienophiles in the Diels-Alder reactions with isoprene (91a) and piperylene (91b) which give 223 (equation 62). Their results have been summarized in Table 6. The reactions proceeded with high endo/exo and regioselectivities. Bidentate co-ordination of the catalyst to both carbonyl groups kept the dienophile in a rigid conformation, which gave rise to the high de values observed. 

Natalini, B., Marinozzi, M., Bade, K., Sardella, R.,Thomsen, C., Pellicciari, R. Preparative resolution of 1-aminoindan-1,5-dicarboxylic acid (AIDA) by chiral ligand-exchange chromatography. Chirality, 2004,16, 314-317. 

Kinbara, K. Kobayashi, Y. Saigo, K. Chiral discrimination of 2-arylalkanoic acids by (lS,2R)-l-aminoindan-2-ol through the formation of a consistent columnar supramolecular hydrogen-bond network. J. Chem. Soc. Perkin Tran. 2000, 2, 111-119. 

A Subtilisin-catalyzed process was developed for the kilogram-scale continuous production of the drug intermediate (R)-l-aminoindan (R)-19e and of the chiral resolving agent (R)-l-(l-naphthyl)ethylamine (R)-19fin PBR [110]. Note the opposite stereopreference of the protease [110] and Upase-catalysis [111-113]. 

Najera el al. have demonstrated that L-prolinethioamides were more effective catalysts for the asymmetric aldolisation of ketones with aldehydes than the corresponding L-prolinamides under solvent-free conditions. " Thus, the use of a novel recyclable L-prolinethioamide, derived from L-proline and (7 )-l-aminoindane, allowed a wide range of chiral aldol adducts to be obtained with a combination of excellent yields and stereoselectivities in general, and at a low catalyst loading of 5 mol % (Scheme 2.24). Furthermore, an intramolecular version of this process could be developed, providing chiral bicyclic diketones with enantioselectivities of up to 88% ee. 

Various chiral amines were tested and the best selectivi-ties and yields were obtained with chiral benzylic amines, particularly with aminoindane derivatives. After acidic hydrolysis, the rhodium-catalyzed C H functionalization led to the aldehyde 58. Whatever the aminoindane derivative used, the yields and selectivities were good and the 7-fluoroaminoindane was the best chiral auxiliary (70% yield, 90% ee). After recrystaUization, the chiral aldehyde 58 was isolated in 99% ee and then used in a Knoevenagel condensation. During this late reaction, the C-20 position has been epimerized to give the more stable thermodynamic anti-diastereoisomer 57 as the major product. The total synthesis... 

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