1- amino-2-indanol

Davies and Reider (1996) have given some details of the HIV protease inhibitor CRDCIVAN (INDINAVIR) for which (lS,2R)-c -amino indanol is required. Indene is epoxidized enantioselectively, using the lacobsen strategy (SS-salen Mn catalyst, aqueous NaOH and PiNO), to (lS,2/ )-indene oxide in a two-phase system, in which the OH concentration is controlled. Indene oxide was subjected to the Ritter reaction with MeCN, in the presence of oleum, and subsequent hydrolysis and crystallization in the presence of tartaric acid gives the desired amino indanol. 

The amino indanol was placed in a 250 mL three-necked round-bottomed flask equipped with a magnetic stirrer bar under nitrogen. Dry methylene chloride (110mL) and triethylamine (6.7 mL) were then added. The reaction mixture was allowed to cool to 0°C before adding a solution of 2-chloro-sulfonyl pyridine (7.1 g in 50mL CH2C12) over 20 minutes. The mixture was stirred at this temperature for 1 hour. 

The Merck group has applied the electrophilic amination using lithium terf-butyl N-(tosyloxy)carbamate 9a to the chiral amide derived from (lS,2/ )-cw-amino-indanol [10] (Scheme 4). Treatment of 10 with n-Buli in THF at -78 °C gave the lithium enolate which was reacted with CuCN. The resulting amide cuprate was allowed to react with 9a. The authors found that a single diastereomer of a-Boc-protected amino amide 11 was formed. The sense of asymmetric induction observed was consistent with preferential approach of 9a from the least hindered face of the enolate. The removal of the chiral auxiliary with refluxing 6N HC1 afforded a-amino acids 12 in good yields and optical purities. 

Jacobsen epoxidation turned out to be the best large-scale method for preparing the cis-amino-indanol for the synthesis of Crixivan, This process is very much the cornerstone of the whole synthesis. During the development of the first laboratory route into a route usable on a very large scale, many methods were tried and the final choice fell on this relatively new type of asymmetric epoxidation. The Sharpless asymmetric epoxidation works only for allylic alcohols (Chapter 45) and so is no good here. The Sharpless asymmetric dihydroxylation works less well on ris-alkenes than on trans-alkenes, The Jacobsen epoxidation works best on cis-alkenes. The catalyst is the Mn(III) complex easily made from a chiral diamine and an aromatic salicylaldehyde (a 2-hydroxybenzaldehyde). 

Not all organic chemists can be Involved in such exciting projects as the launching of a new anti-AIDS drug. But the chemistry used in this project was invented by chemists in other institutions who had no idea that it would eventually be used to make Crixlvan. The Sharpless asymmetric epoxlda-tion, the catalytic asymmetric reduction, the stereoselective enolate alkylation, and the various methods tried out for the enantiomerically pure amino indanol (resolution, enzymatic kinetic resolution) were developed by organic chemists in research laboratories. Some of these famous chemists like Sharpless invented new methods, some made new compounds, some studied new types of molecules, but all built on the work of other chemists. 

The chirality comes from the diamine and the oxidation from ordinary domestic bleach (NaOCl), which continually recreates the Mn=0 bond as it is used In the epoxidation. Only 0.7% catalyst Is needed to keep the cycle going efficiently. The epoxide Is as good as the diol in the Ritter reaction and the whole process gives a 50% yield of enantiomerically pure ds-amino-Indanol on a very large scale. 

Gosh has independently reported a second and-selective aldol addition process (Eq. (8.4)) [6]. Amino indanol derived esters such as 11 are enolized with excess TiCl4 (2 equiv) and Hiinig s base to furnish a brown solution consisting exclusively of the Z-enolate as determined by H NMR spectroscopy. Addition of aldehyde (2 equiv) at -78 °C affords the corresponding aldol adducts 12/13 in 44-97% yield and up to 99 1 antitsyn diastereoselectivity. The optimal substrates in the addition reaction include aliphatic and unsaturated aldehydes. It is interesting to note that the only aromatic aldehyde examined, benzaldehyde, yielded products as a 1 1.l mixture of antv.syn diastereomers. 

Glycidol as a chiral pool member Phenylglycine as a chiral pool member C2 symmetric diamines as chiral pool members Amino-indanols... 

The amino-indanol 286 is the basis for many important asymmetric reagents such as the enolates derived from 293 and the metal complexes such as 295 derived from the dimer 294. These are effective as catalysts for Diels-Alder reactions.53... 

Other amino alcohols occur naturally, including the ephedrine family 52 54. We can add the famous amino-indanol 286 to this collection. 

Modifications to the parent bis(oxazoline) structure have been subsequently disclosed (Fig. 24). Spirobis(oxazoline) 34 derived from amino indanol catalyzes (10 mol %) the enantioselective cycloaddition between cyclopentadiene and acrylimide (-78 °C) in 96.3% ee (endo/exo=44 l) [90]. When the size of the spiro ring (e.g., cyclobutyl, -pentyl, -hexyl) is increased, the resulting structural change progressively degrades the reaction enantioselectivity, demonstrating a relation-... 

A rather different titanium(IV) Diels-Alder catalyst employed a cfs-amino in-danol, prepared in five steps from indene, as the chiral control element [125]. The amino indanol is regioisomeric to the one incorporated into a bisoxazolinyl... 

In 2012, the Chi group demonstrated a diastereoselective NHC-catalyzed access to p-lactam fused spirocyclic oxindoles with an all-carbon quaternary stereogenic center, employing oxindole-derived p,p-disubstituted a,p-unsaturated imines and enals as substrates. The p-lactam products, stable at room temperature, were easily converted to cyclopentenes at 50 °C. An asymmetric example of the annulation reaction was presented with moderate enantioselectivity (89% yield and 51% ee by using the amino indanol derived catalyst), which is probably due to the sterical hindrance of p,p-disubstituted a,p-unsaturated imines (Scheme 7.58). 

In 2013, the Chi group realized an NHC-catalyzed asymmetric p-functional-ization reaction of aldehydes via the transformation of saturated aldehydes to formal Michael acceptors via double oxidation. By using the catalyst derived from the chiral amino indanol triazolium salt in combination with quinone as the oxidant, the p-aryl substituted saturated aldehydes were converted to the o,p-unsaturated acyl azolium intermediates which further reacted with 1,3-dicarbonyl compounds or p-keto esters to generate the corresponding 5-lactones. It was found the use of LiCl and 4 A MS as additives was beneficial to improve the ee s of the products. Notably, the p-alkyl substituted saturated aldehydes were not viable substrates, probably due to the reduced acidity of the p-C—H bonds (Scheme 7.118). 

The amino-indanol-derived triazolium salt F5 was also found to be an efficient precatalyst for the intramolecular Stetter reaction of a-substituted cyclo-hexadienones (Scheme 20.17), furnishing tricyclic products 35 bearing multiple stereocentres in up to 96% yield and with >99% enantiomeric excess. ... 

Recently, Tan and co-workers [95] showed that easily accessible amino-indanol derived guanidines are highly effective strong Brpnsted bases, conveniently employable at low loading, for the desymmetrization of iV-aroyl aziridines (Scheme 14.32) [95]. 

Hydroxy -2-h3rdrindamine (2 - Amino -indanol-l, l-hydroxy-2-aminohydrind )... 

The reported organic bifunctional catalysts possessing both hydrogen bond donor and acceptor moieties are often derived from the cinchona alkaloids. Tan and coworkers developed the simple and readily available amino-indanol 95 as an efficient bifunctional organocatalyst for the enantioselective Diels-Alder reaction of 3-hydroxy-2-pyridones 94 (Scheme 38.26) [40]. Besides maleimides 80, alkyl vinyl ketones were also suitable dienophiles for this catalytic system. 

A metabolic engineering approach [175] and directed evolution techniques [176] were evaluated to avoid side reactions, block degradative pathways, and enhance the desired reaction (conversion of indene to cxs-amino indanol 137 or ds-indanediol). Multiparameter flow cytometry was used to assess indene toxicity, and it was shown that concentrations up to 025 g/1 of indene (0.037g indene per gram dry cell wt.) in batch bioconversions did not influence reaction rate. Using this information, a single-phase... 

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