Chromans chiral

Formylphenoxy)but-2-enoates, available from salicyclaldehydes and 4-bromo-crotonates, undergo an intramolecular Stetter reaction, which, in the presence of a chiral triazolium salt, affords chroman-4-ones with good enantiomeric excesses <96HCA1899>. 

A series of similar reactions was examined in the course of synthesis of substituted chromanes.155 The reactions are thought to proceed through TS M in preference to N because of steric interactions with the phenyl ring on the chiral hydroxylamine. 

For the enantioselective synthesis of chiral chromanes such as 2-213, a chiral Lewis acid complex, formed in situ from Mg(OTf)2 and 2-212, is assumed to catalyze the domino transformation of the phenols 2-210 and the p,y-unsalurated a-ke-toesters 2-211 (Scheme 2.50). 2-213 was obtained in excellent diastereoselectivity, but only in mediocre enantioselectivity. 

Commensurately with the development of various catalyst systems, the Pd-catalyzed G-O cross-coupling has found a number of synthetic applications. Examples include the syntheses of the protein kinase G (PKC) activator (+)-decursin,104 the natural product heliannuol E,105 a chiral 2-methyl chroman,106 and a series of aryloxy and alkoxy porphyrins.107 The Buchwald-Hartwig coupling has also been utilized in the preparation of a heterocycle library.108 Intramolecular O-arylation has also been achieved in the reactions of enolates with aryl halides leading to benzofur-ans.109,110 Finally, a double cross-coupling between an 0-dibromobenzene and a glycol has also been applied for the preparation of benzodioxanes (Equation (16)).1... 

Antus, S. et al., Chiroptical properties of 2,3-dihydrobenzo[6]furan and chromane chromophores in naturally occurring 0-heterocycles, Chirality, 13, 493, 2001. 

The formation of chromane derivatives has also been realised in the palladium catalyzed intramolecular nucleophilic substitution of allyl carbonates (Tsuji-Trost reaction). In most cases the reaction is accompanied by the formation of a new centre of chirality. Using Trost s chiral ligand the ring closure was carried out in an enantioselective manner. The asymmetric allylation of the phenol derivative shown in 4.20. was achieved both in good yield and with excellent selectivity.23... 

The stereochemical consequences of the cyclization of some 3-(2,5-dihydroxyphenyl)pro-pan-l-ols (247) have been investigated, with a view to optimizing the chiral economy of a tocopherol synthesis from (S)-chroman-2-carboxylic acid (81JOC2445). It was observed that acid-catalyzed dehydration occurred with retention of configuration and it was proposed (79JA6710) that the process involved the formation of a hemiketal through nucleophilic attack by the side-chain hydroxy group on the keto tautomer. 

Synthesis of the enantiomerically pure (5)-chroman-2-carbaldehyde (257) follows a similar route to the above, but the chirality is introduced through the ketone (256) (82CC205). A particularly interesting feature of this synthesis is the derivation of the diol (255) from 2-methyl-3-(2-furyl)propenal using fermenting baker s yeast. Furthermore, the fermentation also produces the chiral alcohol (258), a source of the C15 unit which is the second component along with the aldehyde (257) in an a-tocopherol synthesis. 

An intramolecular radical cyclization provides the basis for an asymmetric synthesis of 3-aminochromans. The chirality of the cyclization precursor 473 is derived from either L- or D-serine, and the separable regioisomeric chromans, S)-tert-buty 5-acetylchroman-3-ylcarbamate and R)-tert-butyl 7-acetylchroman-3-ylcarbamate arise due to two possible cyclization modes A or B of the radical intermediate 474 (Scheme 105) <2003OL4253>. 

The synthesis of the optically active chroman 489 can be achieved by use of a catalytic asymmetric tandem oxa-Michael addition Friedel-Crafts alkylation sequence between 3-methoxyphenol and (/. (-methyl 2-oxo-4-phenylbut-3-enoate. The chiral C2-symmetric box managanese(n)- complex 490 exerts excellent stereocontrol upon the reaction (Equation 200) <20030BC1953>, whereas only moderate enantioselectivity is observed in the presence of a chiral C2-symmetric 2,2 -bipyridyl copper(n)- complex (42% = ee) <20050L901>. 

A sequence of allylation, epoxidation and an acid-mediated 6-exo cyclisation converts salicylaldehydes into 2-hydroxymethyl-2-methyl-27/-[l]benzopyrans. A bicyclic chroman arising from attack of the hydroxymethyl group on the intermediate benzylic cation has been isolated <02SL322>. A twelve-step enantioselective synthesis of a 2-hydroxymethyl-2-methylchroman with an overall yield of 48% uses related methodology and introduces the chirality through an asymmetric Sharpless epoxidation <02JCS(P1)496>. 

The asymmetric intramolecular crossed benzoin reaction catalysed by a chiral triazolium salt has been used to synthesise 3-hydroxychroman-4-ones 34 in good to high yields and ee. The absolute configuration at the quaternary stereocentre C-3 has been shown to be S by X-ray analysis of the camphanyl ester <06SL2431>. Both enantiomers of 2-(2-phenylethyl)chroman-4-one, flindersiachromanone, have been obtained from racemic l-phenylhex-5-en-3-ol after resolution via lipase-catalysed acetylation <06H(68)483>. 

The asymmetric hydrogenation of chroman-4-ones has been achieved in quantitative yield and with up to 98% ee using a chiral Ru catalyst <06JA8724>. 

Although diastereoselective intramolecular al-koxypalladations have been investigated intensively and have found application in synthesis (see above), there are few examples of enantioselective alkoxypalladations [2bJ. For instance, Hosokawa et al. were able to cyclize unsaturated phenol derivatives of type 62 in the presence of chiral (// -allyl-PdOAc complexes, i.e. 63), but only with modest enantioselectivities. Under the same conditions the conversion of the phenol 65 to chroman 66 (a compound related to vitamin E) proceeded in acceptable yields, but with only low asymmetric induction. Newer results by Uozumi et al., for instance the Pd-catalyzed cyclization of 67 to 68 in the presence of a chiral bis-oxazolin ligand [15], show that much higher enantioselectivities can be achieved, at least for certain substrates. 

Deshpande, P. R Baker, D. C. A simple approach to the synthesis of the chiral substituted chroman ring of calophyllum coumarins. Synthesis, 1995, 630-632. 

This chapter deals with the total synthesis of vitamin E (1) comprising a Pd(II)-catalyzed domino Wacker-Heck reaction as the key step, which allows not only the formation of the chiral chroman framework with an enantioselectivity of 96 % ee but also the simultaneous introduction of part of the side chain. ... 

Several enantioselective approaches to vitamin E (1), based on resolution of the products, the use of enantiopure natural building blocks, auxiliary controlled reactions and asymmetric oxidations have been described. In addition, a palladium-catalyzed asymmetric allylic alkylation reaction to build up the chiral chroman framework has been employed by Trost. Tietze and coworkers have developed asymmetric syntheses of the chiral chroman moiety using either the selective ally-lation of an alkyl methyl ketone or a Sharpless dihydroxylation as the key step. However, none of these methods is efficient enough for an industrial approach. ... 

According to these lines, Tietze and coworkers have recently shown that the chiral chroman moiety in vitamin E (1) can be prepared in a much more efficient way with the concurrent introduction of part of the side chain using a novel enantioselective domino Wacker-Heck Process. ... 

It is assumed that in the first step of the domino Wacker-Heck Reaction the chiral catalyst generated from Pd(II) and an enantiomeri-cally pure BOXAX-ligand 5 coordinates enantiofacially to the aliphatic double bond in 6. The resulting intermediate 7 further reacts by oxypalladation to give 8 with enantioselective formation of the chroman. A p-hydride elimination is not possible because of the absence of H-atoms in the P-position. Thus, the palladium species then forms intermediate 11 in a subsequent Heck reaction with methyl acrylate (10) or methyl vinyl ketone (9) providing the final product 12 and Pd(0) after a P-hydride elimination. 

This domino Wacker-Heck reaction is the key step of this total synthesis. In the presence of catalytic amounts of Pd(OTFA)2, the chiral ligand (S,S)-Bn-BOXAX (5) and j -benzoquinone (13) as reoxidant, phenol 19 first undergoes an intramolecular enantioselective Wacker oxidation and then reacts with methyl vinyl ketone (9) in a Heck reaction to afford chroman 22 with part of the vitamin E side chain in 84 % yield with 97 % ee. 

A few other examples are listed in Scheme 49 intramolecular addition of amine giving a good synthesis of (/ )-(-P)-camegine, synthesis of chiral butenolides by carbonation of vinylic carbanions and conjugate additions of cuprates yielding chiral chromans. ... 

Chiral chromans are redueed stereoselectively by oxazaborolidine-catalyzed hydroboration to give the potent antiarrhythmia agent MK-0499, which acts as a potassium channel blocker [46]. 

The large-scale pilot plant preparation of the chiral aminochroman antidepressant ebaizotan (also known as NAE-086) was developed by H.J. Federsel and co-workers. The structural features of the target included a disubstituted chroman skeleton, a stereocenter, as well as a non-symmetrical tertiary amine moiety at the C3 position and a secondary carboxamide group at C5. The backbone of the target molecule was constructed using the Perkin condensation of 2-hydroxy-6-methoxybenzaldehyde with hippuric acid under mild conditions. 

Chroman-4-one 6. To a stirred solution of 4-(2-formylphenoxy)-but-2-enoate 4 (275 mg, 1.25 mmol) and chiral catalyst 5 (118 mg. 0.25 mmol) in THF (40 mL) were added K2C03 (17.5 mg) at 20°C. After 24 h the mixture was diluted with water, extracted with CH2CI2 and the solvent evaporated. The residue after chromatography (silica gel Et20 pentane 1 1) gave 200 mg, of 6 (73%) yield, 60% ee, config R, ao20 = -4.6°. 

Trost, B.M. et ah. Synthesis of chiral chromans by the Pd-catalyzed asymmetric allylic alkylation (AAA) scope, mechanism, and applications, J. Am. Chem. Soc., 126, 11966, 2004. 

Chromans. - 2,4-Diethoxychromans (78) (mainly cis) represent a new type of chroman and have been prepared in high yield from a phenol (but not a deactivated phenol) and malonaldehyde bis(diethyl acetal) in the presence of SnCU they are converted into the benzopyrylium salts (79), in excellent yield, by treatment with perchloric acid. A Wittig-Horner reaction of the chiral phosphoryl ( S)-sulphoxide (81) and the ketone (80) gave the chiral sulphoxide (82), which was cyclized by aqueous alkali to a mixture which contained 22% diastereoisomeric excess of (25 )-chroman (i )-sulphoxide. This was converted, in three steps, into the aldehyde (83), which is a useful synthon for a-tocopherol. ... 

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