Indenes indanols

The cooxidation of thiophenol with indene by air in hydrocarbon solvents provides l-hydroperoxy-2-phenylthioindane 84 in 77% yield. Subsequent rearrangement afforded a mixture of trans and cis 2-phenylsulphinyl-l-indanols 85148 149 (equation 47). 

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

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. 

Prepare 6-methoxy-l-indanone (I) (JCS 1986(1962)) using polyphosphoric acid made by diluting 500 g of the commercial acid with 120 g 85% phosphoric acid. 2.5 g (I) in 176 ml ether and reflux one hour with 0.27 g lithium aluminum hydride. Cool and carefully add water and filter when bubbling stops (can use Celite filter aid). Dry and evaporate in vacuum and store twelve hours at -15° (under N2 if possible) to precipitate the white 6-methoxy-l-indanol (II) (recrystallize-n-hexane). 2.5 g (II) in 73 ml benzene and reflux one-half hour with 0.2 g p-toluenesulfonic acid. Cool, add water and separate the phases. Extract the aqueous phase with ether and combine with benzene phase and dry, evaporate in vacuum to get 5-methoxy-indene (III) (can distill 110-45/10). 1.53 g (III) and 1.39 g N.N-diethyl-aminoethyl-Cl.HCI in benzene (prepare the free base in benzene as described previously). Reflux four hours with 0.42 g sodamide, cool, wash with water and dry, evaporate in vacuum to get the indene analog of 6-methoxy DET as a dark liquid (can crystallize as oxalate). Alternatively, dissolve 2.51 g (III) in ether and treat (under N if possible) with 12 ml 1.6M buty-Li in hexane at 0-10°. After two hours cool to -30° and add 12 ml more of butyl-Li. Add ether suspension of 2.5 g N,N-diethylaminoethyl-CI. HCI over one-half hour and warm to room temperature. Filter, evaporate in vacuum to get the 6-methoxy-DET analog. 

Enantiomerically pure epoxides and diols, readily available through the asymmetric epoxidation and asymmetric dihydroxylation reactions, are ideal precursors to prepare cis-amino alcohols via the Ritter reaction. " " A Merck group has shown that indene oxide 175a can be converted effectively to c/i-l-amino-2-indanol, a key fragment of the HlV-protease inhibitor Indinavir via the cis-... 

Co-oxidation of indene and thiophenol takes place readily if the reactants in benzene solution are shaken with oxygen at temperatures in the range 20° to 40°C. (7). The major primary product has been shown to be frans-2-phenylmercapto-1 -indanyl hydroperoxide, I, which rearranges spontaneously to the two racemes of frans-2-phenylsulfinyl-l-indanol, II (8), and a tentative reaction scheme involving a three-step radical chain based on the suggestion of Kharasch, Nudenberg, and Mantell (11) was proposed for the formation of I. These three products accounted for 86% of the oxygen absorbed. 

Racemic substituted aminoindanol 9 was synthesized in a 5-step sequence by nitration of 1-indanone, followed by ketone reduction and dehydration to give 6-nitro-l-indene and subsequent epoxidation of the olefin and final regioselective animation (Scheme 8.5). Optically pure (IR,2R)-and (1 S,2S)-6-nitro-1 -amino-2-indanol 9 were eventually obtained by resolution with mandelic... 

Research groups at Sepracor53 54 and Merck50-52 independently developed similar strategies to access (lS)-amino-(2R)-indanol. Both processes used Jacobsen s Mn-(salen) catalyst (MnLCl, 2g)42-44,55 for indene epoxidation, followed by chirality transfer of the C-0 bond of indene oxide 26 to obtain enantiopure (15)-amino-(2/f)-indanol (Scheme 24.2). 

The Sepracor group demonstrated that (l/ ,2S)-indene oxide 26 could be prepared from readily available indene 25 in the presence of 1.5 mol% of (R,R)-MnLCl and 13% NaOCl in dichlo-romethane in 83% yield and 84% ee (Scheme 24.2). Chiral indene oxide 26 was then subjected to nucleophilic opening with ammonia to provide /ram-aminoindanol, which was transformed without isolation to its benzamide under the Schotten-Baumann condition (83% ee, >99.5% ee after recrystallization). The optically pure trans-benzamidoindane was then converted to the optically pure benzaoxazoline 27 by exposure to 80% H2S04, followed by addition of water to give cis-1-amino-2-indanol.53 54 The sequence was demonstrated on multi-kilogram scale to prepare optically pure (IR, 2.S )-1 in 40% yield from indene. 

Indanyl)-phenol 16 was obtained by reacting p-methoxy-phenyl-acetic acid ethyl ester with benzylchloride to form a-benzyl-p-methoxyphenyl ethyl acetate, saponification into the acid, conversion of the acid with thionylchloride into the chloride, cyclization to 2-p-methoxy-phenyl-l-indanone, NaBH4 reduction to 2-p-methoxyphenyl-l-indanole, dehydration with p-toluene-sulphonic acid in toluene to 2-p-methoxyphenyl-indene, catalytic hydrogenation to 2-p-methoxyphenyl-indene, and treating the ether with HBr [Eq. (5)]. 

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... 

Naphthalene dioxygenase carried out dioxygenation of indene to ris-(l R,2S)-indandiol, monooxygenation to lS-indenol, and in addition dehydrogenation of indan to indene. Further details of this and other reactions of indanol are given in Chapter 6, Section 6.2.3. 

It has been noted in Section 4.4.1.1 that naphthalene dioxygenase from a strain of Pseudomonas sp. also carries out enantiomeric monooxygenation of indan and dehydrogenation of indene (Gibson et al. 1995), and the stereospecific hydroxylation of (R)-l-indanol and (S)-l-indanol to rfs-indan-l,3-diol and trans (lS,3S)-indan-l,3-diol (Lee et al. 1997) the indantriols are also formed by further reactions. Essentially comparable reactions have been observed with Rhodococcus sp. strain NCIMB 12038 (Allen et al. 1997). 

Protease inhibitors are well-characterized chiral drugs in terms of their mechanism of action. An important new class of protease inhibitors comprises molecules designed to treat HIV infection. In particular, indinavir sulfate (CRIXIVAN, Merck and Co., Inc.) contains five chiral centers that must be of a specific orientation for the molecule to have the desired therapeutic effect. Manufacturing processes for these compounds involving chemical synthesis steps can be quite inefficient, due to yield reduction caused by racemization at each step where a chiral center is formed. A key intermediate in the synthesis of CRIXIVAN is cis-(lS,2R)-l-amino-2-indanol [(-)-CAI], an indene derivative that contributes two chiral centers to indinavir sulfate (Fig. 1). To circumvent the technically demanding chemical synthesis of (-)-CAI and reduce product loss, Merck scientists conceptualized a bioconversion process in which indene is oxidized to one of three derivatives that can serve as precursors to (-)-CAI cis-(lS,2R)-indandiol, trans-(lR,2R)-indandiol, or (lS,2R)-indan oxide. Oxygenases that have been identified in isolates of the genus Pseudomonas and Rhodococcus can catalyze this transformation. 

When the hydroperoxide intermediate formed in the co-oxidation of 2-naphthaIenethiol and indene is allowed to decompose in the presence of 2-(4-chlorophenylmercapto)-l-indanol, none of the latter was oxidized. This would suggest an intramolecular transfer of the peroxidic oxygen at the sulphide sulphur. 

Indene Oxide (ChiRex). The epoxidation of indene is an attractive route to cis l-amino-2-indanol, an intermediate in the Crixivan synthesis (HIV protease inhibitor of Merck) and ligand for BH3 reductions of ketones (60a,61). 

Potassium bromide/bromine 2-Bromo-l-indanols from indenes s. 18,197... 

Hydroboranation of substituted indene gives the 3-indanol [666, 669]. Asymmetric induction with optically active pinene results in a larger enantiomeric excess of the more interesting enantiomer [670]. 

An aq. soln. of bromine and KBr added during 1 hr. at a diminishing rate with vigorous stirring to an aq. emulsion of indene while the temp, is raised from 55 to 90° 2-bromo-l-indanol (Y up to 95%) suspended in a soln. of Na in methanol, and refluxed 8 hrs. under N2 l-methoxy-2-indanol (Y ca. 90%) added dropwise to 40%-H2SO4 with simultaneous steam-distillation of the product 2-indanone (startg. m. f. 733) (Y 85-90%). W. Treibs and W. Schroth, A. 639, 204 (1961). 

Arene.. dioxygenases catalyze reactions other than dihydroxylation of aromatics. For example, toluene dioxygenase catalyzes monooxygenation of indene and indan to 1-indenol and 1-indanol, respectively [382], oxidation of polyhalogenated compounds such as trichloroethylene [eq. (24)] [363, 388-390], and stereoselective sulfoxidation of sulfides [391, 392]. 

This mechanism, however, does not explain the behavior of the other alkenes studied. Thus indene gave two amino alcohols. Only one of them, trans-2-(dimethylamino)-l-indanol, could... 

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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