Chromane, asymmetric 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 reaction of salicylaldehydes with a,P-unsaturated compounds which can lead to chromenes, chromans and other heterocycles has been reviewed <07OBC1499> and details of their reaction with allenic esters and ketones have been published <07CEJ3701>. A proline-catalysed benzoic acid-promoted asymmetric synthesis of chromene-3-carbaldehydes involves a domino oxa-Michael - aldol reaction with a,P-unsaturated aldehydes the ee range is 83-98% (Scheme 11) <07CEJ574>. 

Asymmetric synthesis of a chroman. Solladie and Moine have effected an en-antiospecific synthesis of the chroman-2-carboxaldehyde 7, a key intermediate in the synthesis of a-tocopherol, from (R)-( +)-l. The phosphonate 2, derived from 1, undergoes a Wittig-Horner reaction with the dimethyl ketal of pyruvaldehyde to afford the optically active vinyl sulfoxide 3. Condensation of the aldehyde 4 with the lithio derivative of 3 affords, after silyl deprotection, the allylic alcohol 5 as the only diastereoisomer. This... 

For the asymmetric synthesis of the 2-substituted chromane 7 via the intramolecular Michael addition reaction of 6, Merschaert et al. also employed natural cinchona alkaloids such as HCD as catalysts (Scheme 9.3) [3]. Here again, the 9-0 functionalization and dehydroxylation of the natural alkaloid showed a large negative effect, indicating that the presence of the 9-OH group is needed to achieve both good kinetics and enantioselectivity. Moreover, C3 modifications of this parent alkaloid did not lead to any significant improvement in the results in terms of the enantioselectivity and catalytic activity. 

Saito, N., Ryoda, A., Nakanishi,W. eta/. (2008) Guanidine-catalysed asymmetric synthesis of 2,2-disubstituted chroman skeletons by intramolecular oxa-Michael addition. European Journal of Organic Chemistry, 2759-2766. 

Most AFC alkylation reactions are focused on relatively reactive furans, pyrroles, and indoles, whereas benzene derivatives are much less explored. The Wang group reported the organocatalytic asymmetric synthesis of chromane and dihydrobenzopyrane derivatives 121 from readily available 1-naphthols and a,p-unsaturated aldehydes by the AFC alkylation/cyclization cascade reaction (Scheme 6.49). The process appeared to have a broad substrate... 

A catalytic triple domino Michael-aldol-oxa-Michael reaction of acetaldehyde with ( -2-(2-nitrovinyl)phenols catalyzed by (R)-2- diphenyl [(trimethylsilyl)oxy] methyl pyrrolidine followed by a sequential one-pot Wittig, Michael/Wittig-Horner reactions with PPh3=CHC02Et was applied to the asymmetric synthesis of polyfunctionalized chromans (14EJO3076). 

Shortly after, Merschaert et al. developed a new asymmetric synthesis of simple 2-substituted chiral chromanes by the intramolecular addition of a phenolic nucleophile to an a,p-unsaturated ester catalysed by Cinchona alkaloids.The best ee values (80%) were obtained with cinchonine and its C-3 modified derivatives. 

Scheme 7.18. Supported pyrrolidine catalysts in asymmetric synthesis of chromanes.

Later, Ramachary and Sakthidevi reported for the first time the organo-catal)Aic cascade approach to the asymmetric synthesis of functionalised chromans via Barbas-List aldol-acetalisation reaction, as depicted in Scheme 2.28. The reaction of acetone with 2-hydro ybenzaldehyde under trans-4-OH-L-proline-catalysis in NMP as solvent furnished the corresponding aldol/lactol intermediate which upon treatment with p-TSA in methanol in one-pot furnished the selectively frans-2-metho y-2-methyl-chroman-4-ol in 55% yield and 77% ee, as shown in Scheme 2.28. 

SCHEME 1.11 Organocatalytic asymmetric synthesis of chromane derivatives [36]. 

A series of functionalized chromanes were generated from a C—H alkylation reaction between 1-naphthol and a series of a,p-unsaturated-a-keto esters (Scheme 2.22) [27]. The chemistry was carried out under very mild conditions using an organocatalyst and was remarkably insensitive to the electronic composition of the a-keto ester. Heteroaromatic examples were also successfully functionalized using this approach. The chemistry was successfully extended to 2-naphthol and excellent conversions (up to 90%), and high enantioselectivities were obtained (up to 96% ee). In related work, a simple proline derivative was also able to promote the asymmetric synthesis of chromane derivatives (Scheme 2.23) [28]. 

SCHEME 2.23 Asymmetric synthesis of chromane derivatives using a proline derivative as an organocatalyst [28],... 

Recent studies revealed that (2S)-tocopherols have no antioxidant effect in biological systems because they are not accepted as substrates by the a-tocopherol transfer protein (TTP), which is responsible for the transport of vitamin E into the tissue. As a result, the enantioselective synthesis of the a-tocopherol became attractive, and several groups have reported on its asymmetric synthesis. In addition, Tietze and co-workers reported on an enantioselective palladium-catalyzed total synthesis of vitamin E by employing a domino Wacker-Heck reaction (Scheme 21.15). ° In their study, reaction of 64 with methyl acrylate in CH2CI2 with catalytic amounts of Pd(TFA)2 (TEA = trifluoroacetate), the chiral ligand (5,5)-Bn-BOXAX 65, and p-benzoquinone afforded the desired chroman 66 with 96% ee in 84% yield. The enantioselective cascade reaction described therein provided the efficient construction of the chroman firamework of vitamin E 67 with concomitant introduction of part of the side chain in high yields and high enantioselectivities. 

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>. 

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. 

A study of the synthesis of chromans from allylic carbonates involving Pd-catalysed asymmetric allylic alkylation has established that the addition of acetic acid results in a pronounced increase in enantioselectivity. Furthermore, (E) allylic carbonates afford (R) chromans and the (Z) substrates the (S) heterocycle (Scheme 13) <03JA9276>. This approach to chromans has been combined with a radical epoxide cyclisation in a total synthesis of (-)-siccanin <03AG(E)3943>. 

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. 

A significant study of the synthesis of chiral chromans by the Pd-catalysed intramolecular asymmetric allylic alkylation of readily available phenol allyl carbonates has established the optimum conditions for this highly efficient method and demonstrated its value by the total syntheses of (+)-clusifoliol and (-)-siccanin (Scheme 6) <04JA11966>. A biomimetic enantioselective synthesis of (-)-siccanin also features this approach to the chroman moiety <04JA12565>. 

The chroman moiety is a constituent of some important natural products, e.g. the tocopherols and canabinoids. a-Tocopherol 12 (vitamine E) occurs in wheatgerm oil. It contains three asymmetric centres (C-2, C-4 and C-8 ) which each have an (/ )-configuration. a-Tocopherol was prepared by a stereoselective synthesis [44]. 

Pd-catalysed coupling of an o-iodophenol with an a,p-enyne features together with a Sharpless bishydroxylation in an enantioselective route to chromans of value in the synthesis of vitamin E <97SYN877>. An alternative approach to precursors of the tocopherol incorporates an asymmetric allylation <97SL1049>. A conversion of a-tocopherol to y-tocopherol involves the photo-decarboxylation of y-tocopherol-S-carboxylic acid <97SL208>. 

The first asymmetric intramolecular process was described by Enders in 1996, who used triazolium salt 143 in the synthesis of chiral chroman-4-one derivatives. Moderate yields (22-73%) and enantioselectivities of up to 74% were obtained (Scheme 1.35) [48]. 

Unlike the intermolecular Stetter reaction, significant progress has been made in the asymmetric intramolecular variant of the reaction since first examples reported by Enders et al. in 1996 towards the synthesis of optically active chroman-4-one derivatives using chiral triazohum salts as catalysts [306]. Recently, Rovis group... 

A synthetically powerful variant of the asymmetric FCA reaction via Michael addition involves cascade processes in which multiple catalytic events occur subsequentially. The approach has been efficiently employed in the synthesis of chromanes and polycyclic analogues via enantioselective annulation reactions. 

Vitamin E (a) L. F. Tietze, J. Gorlitzer, A. Schuffenhauer, M. HUbner, Eur. J. Org. Chem. 1999, 1075-1084. Enantioselective synthesis of the chromane moiety of vitamin E. (b) L. F. Tietze, J. Gorlitzer, Synlett 1997, 1049-1050. Preparation of enantiopure precursors for the vitamin E synthesis. A comparison of the asymmetric allylation of ketones and the sharpless bishydroxylation. (+)-Hydroxymyoporone (c) L. F. Tietze, C. Wegner, C. Wulff, Chem.-Eur. J. 1999, 5, 2885-2889. First total synthesis and determination of the absolute configuration of the stress factor (+)-hydroxymyoporone. 5,6-Dihydrocineromycin B (d) L. F. Tietze, L. Vblkel, Angew. Chem. Int. Ed. 2001, 40, 901-902. Total synthesis of the macrolide antibiotic 5,6-dihydrocineromycin B. 

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