Indene oxides

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. 

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-... 

Only compounds of type I and II, which contain both metal and sulfur, were found to act as inhibitors. Compounds III and IV, for example, were ineffective. The inhibition of indene oxidation by zinc dithio-phosphates was considered to be a key result in this work since it rules out the intermediate formation of free thiyl radicals. There is adequate evidence (2, 9, 16, 17, 22) that thiyl radicals, including (RO)2PS2, add rapidly to olefins and that in the presence of oxygen the following sequence of reactions would occur. 

A one-step synthesis of isochromene itself has been reported from indene oxide (191) (66CC415). Irradiation of the epoxide in benzene affords two products, isochromene and indan-2-one, in similar quantities. It was proposed that initial fission of the carbon-carbon bond of the three-membered ring is followed by 1,4- or 1,2-hydrogen migration (Scheme 36). 

On the other hand, indene oxide and 1,2-epoxytetralin (Eq. 327). undergo reduction with no difficulty on treatment with sodium in moist ether. . n i The phenyl ring not only greatly enhances the eufioeptibility of the epoxide function to attack by hydrogen, but also directs addition exclusively to the benzylie portion. Similar results were obtained when reduction was conducted with sodium in liquid ammonia.1 ... 

Addition of water to indene oxide,1 1,2-dihydronapMbuldihydronaphthalene oxide, in the presence of... 

In a similar manner, thiophonol has been condensed with etbyleno oxide itself,1230 with cyclohexene oxide,1230 and more recently with indene oxide.684 The last undergoes addition preferentially at the henscylic epoxide carbon atom Both alicyclic epoxides (Eqs. 663 and 664) are cleaved to 2-phenylthiocycloalkanols possessing fazna-con-figuration. 

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. 

A complementary approach to the synthesis (1R,2S)-1 has been developed by Merck using (.S, .S )-Mnl.CI catalyst in a hypochlorite medium to provide (IS, 2/0-indene oxide 26. This intermediate was converted without isolation to r/.v-aminoindanol in a stereoselective and regioselective manner using Ritter technology (Scheme 24.2). Several key issues, detailed later in this chapter, have been addressed and resolved in both Jacobsen s AE52 and Ritter technology50 to develop a reproducible and practical large-scale process for the synthesis of enantiopure d.s-aminoindanol. 

The asymmetric oxidation of indene to the corresponding epoxide (Equation 24) is carried out commercially by Sepracor on a small scale. Chiral indene oxide is an intermediate in the synthesis of crixivan (an HIV protease inhibitor). Reaction is carried out at 5°C with moderately high turnover numbers in the presence of an exotic donor ligand ( P3NO , 3-phenylpropylpyridine N oxide) and sodium hypochlorite as the terminal oxidant. A similar epoxidation of a simple cis olefin (Equation 25) leads to an enantiomerically pure amino-alcohol used in the synthesis of taxol, a potent anticancer drug. 

Kinetic resolution has been reported for dihydronaphthalene oxide and indene oxide upon irradiation in the presence of catalytic amounts of a Ru(salen)(NO) (3) complex (Scheme 10.6) [7]. 

The opening of cyclohexene oxide with monochloroacetic acid is not a selective reaction bis(Zra/is-2-hydroxycyclohexyl)ether mono(chloroacetates) and trans-2-(chloroacetoxy)cyclohexanol are formed. In an aprotic solvent with benzoic acid, indene oxide gives only trans product. The reaction of oxirane with monochloroacetic acid esters is shown in Eq. 313. ... 

Due to the demand for inexpensive anti-HIV agents, several reactions for the synthesis of Indinavir (70, an HIV protease inhibitor of Merck Co.) have been reported. Enantioselective epoxidation of simple alkenes with bleach is achievable in the presence of the Mn " complex 69 possessing a well-designed chiral salen ancillary [69]. Scheme 20 exemplifies its application to the synthesis of Indinavir (70), by way of indene oxide (68) in 88 % ee [69]. This method is also useful for the asymmetric synthesis of a chromene epoxide in 97 % ee serving as an intermediate for Lemakalim, a K" -channel opening agent [70]. 

Mechanisms of acid-catalyzed hydrolysis of 1-phenylcyclohexene oxides, indene oxides and 1,2,3,4-tetrahydronaphthalene-l,2-epoxides 264... 

Acid-catalyzed hydrolysis of indene oxides transition-state effects on stereochemistry of diol formation 266... 

ACID-CATALYZED HYDROLYSIS OF INDENE OXIDES TRANSITION-STATE EFFECTS ON STEREOCHEMISTRY OF DIOL FORMATION... 

The cis/trans hydrolysis ratio from the acid-catalyzed hydrolysis of indene oxide (53a, Scheme 17) is 75 25,62,63 and that from acid-catalyzed hydrolysis of 5-met-hoxyindene oxide (53b) is 80 20.61 Thus, the introduction of a methoxy group into position 5 does not result in any significant change in the cis/trans hydrolysis ratio. There is evidence that 54b, which is stabilized by the 5-methoxy group, is sufficiently stable to be trapped by external nucleophiles. The very similar cis/tram diol product ratio from acid-catalyzed hydrolyses of both 53a and b suggest that 54a is also a discrete intermediate. 

The cis and trans diols 55b and 56b are sufficiently reactive in dilute acid solution to undergo equilibration, and the tram diol was determined to be more stable than the cis diol by a factor of 3. In this system, therefore, the major diol from acid-catalyzed hydrolysis is the less stable isomer. This result contrasts with the results from acid-catalyzed hydrolysis of phenyl-substituted cyclohexene oxides, where the major cis diol product is also more stable than the corresponding trans diol. In the hydrolysis of indene oxides 53a, b, therefore, effects that are present in the transition state but absent in the products must play major roles in controlling the cis/trans product ratio. 

The stereochemical outcomes of the acid-catalyzed hydrolyses of 1,2,3,4-tetrahy-dronaphthalene 1,2-oxide 59a and its 6-methoxy derivative 59b (Scheme 18) are quite different from those of the corresponding indene oxide systems. For example, acid-catalyzed hydrolysis of 59a yields only 5% of cis diol 61a and 95% of tram diol 62a.66 However, acid-catalyzed hydrolysis of its 6-methoxy derivative 59b yields 80% of cis diol 61b and 20% of tram diol 62b.67 One might argue that carbocation 60a does not have a sufficiently long lifetime compared to solvent relaxation, whereas 60b does, and that this difference in lifetime leads to different mechanisms... 

Whereas indene oxide and its 2-hydroxy-1-indanyl carbocation are each calculated to occupy one stable conformation, tetrahydronaphthylene oxide 59a and carbocation 60a are each calculated at the B3LYP/6-31G level of theory to have two minimum-energy conformations, shown in Scheme 19. The mechanism for hydrolysis of this system should therefore take into consideration these additional conformations. 

The [Mn(salen)] -catalyzed epoxidation of indene has also proven to be synthetically useful in various contexts. Enantio-enriched indene oxide, produced in 84-86% ee by AE of the corresponding olefin, is a precursor to important building blocks including cfs-aminoindanol through a Ritter reaction (Scheme 10)... 

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