Indanols synthesis

Phenols, pAfa values of 586-589 Phenothiazine oxides, mass spectra of 130 2-Phenylsulphinyl-l-indanols, synthesis of 256... 

Ritter-Type Process for ds-l-Amino-2-Indanol Synthesis.465... 

Ritter-Type Process for c/s-1-Amino-2-Indanol Synthesis... 

Imidazoles 775 /J-Iminosulphones 640 /J-Iminosulphoxides, synthesis of 69 Inclusion compounds 59, 287 Indanols 256 Indanones 338 Indenes 267 Indoles 323... 

SYNTHESIS To a solution of 22 g of KOH in 250 mL of hot EtOH, there was added 50 g of 4-indanol and 75 g methyl iodide. The mixture was held at reflux for 12 h. There was then added an additional 22 g KOH followed by an additional 50 g of methyl iodide. Refluxing was continued for an additional 12 h. The mixture was poured into 1 L H20, acidified with HC1, and extracted with 3x75 mL CH2C12. The pooled extracts were washed with 5% NaOH, then with dilute HC1, and the solvent was removed under vacuum. The residue of crude 2,3-(trimethylene)anisole weighed 56.5 g and was used without further purification in the following reaction. 

Phenol annelation.1 This modified methyl vinyl ketone can be used for synthesis of 5,6,7,8-tetrahydro-2-naphthol or 5-indanol by reaction with the lithium enolate of cyclohexanone or cyclopentanone, respectively. The former reaction is formulated in equation (I). 

Since the discovery of cis-1 -amino-2-indanol as a ligand for human immunodeficiency virus protease inhibitors and the development of a practical industrial process for the synthesis of either ris-isomers in enantiopure form, the remarkable properties of the rigid indane platform have been used extensively in an ever-increasing number of asymmetric methodologies. In addition to the use of this amino alcohol as a chiral auxiliary and ligand for asymmetric synthesis, it has found application as a useful resolution agent. Applications include amines, carboxylic acids, and alcohols. 

One of the few industrial examples of the asymmetric synthesis of halohydrins is in a process to the human immunodeficiency virus (HIV) protease inhibitor, Indinavir.190 The y,8-unsaturated carboxamide 23 is smoothly converted into iodohydrin 24 (92%, 94% de) (Scheme 9.34). (For more on the chemistry of the indanol, see Chapter 24.)191... 

Enantiomerically pure d.v-1 -amino-2-indanol and its derivatives have been used as ligands in numerous catalytic asymmetric carbon-hydrogen, carbon-carbon, and carbon-heteroatom bond formation reactions. The conformationally constrained indanyl platform has emerged as a particularly valuable backbone in a variety of catalytic processes leading to high levels of asymmetric induction. The aminoindanol 1 has also been used as a resolution agent (Chapter 8) as well as a chiral auxiliary (Chapter 24). For the synthesis of 1 see Chapter 24. 

This chapter focuses on the importance of cis-1 -amino-2-indanol as a chiral template in the development of new methodologies for the asymmetric synthesis of organic compounds. Other chiral auxiliaries are discussed in Chapter 23. The use of the amino alcohol 1 in resolutions is discussed in Chapter 8, whereas applications of 1 as a ligand are in Chapter 17. 

This alkylation strategy has been successfully implemented to the diastereoselective synthesis of a number of biologically active compounds,17 19 32 72 73 including the orally active HIV protease inhibitor Crixivan (>95% de)17-19 and nucleoside antibiotic (+)-sinefungin (51) (>99% de).72 The C-6 amine stereochemistry of (+)-sinefungin was set by a highly diastereoselective allylation of (lS,2/ )-l-amino-2-indanol-derived oxazolidinone 52 (Scheme 24.10). 

The chiral sulfonamide 45, which can be prepared in two steps from commercially available (I R,2S)-cis-1 -amino-2-indanol (44), was introduced by Ghosh and Onishi for the synthesis of enantiomerically pure anft -aldol products via titanium enolate19a (Scheme 2.2q). 

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). 

Senanayake, C. H. Applications of c/5-l-Amino-2-indanol in Asymmetric Synthesis, Aldrichimica Acta 1998, 31, 3-15. 

Meador and Wagnerhave reported an efficient photochemical synthesis of indanols (75) by the cyclization of the ketones (76). The process ultilizes the variant of the Norrish Type II reaction involving 6-hydrogen abstraction by the excited carbonyl group. The kinetic information collected for the reactions... 

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