Chroman enantioselective synthesis

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. 

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>. 

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>. 

An alkenyl phenol was the starting material for the enantioselective synthesis of the secondary metabolites of endophytic fungus Paecilomyces sp., paecilins A and B. The spectroscopic data of these synthetic chroman-4-ones... 

SoUadie and Moine have reported the highly diastereoselective reaction between the a-lithiated-a,P-unsaturated sulfoxide (51) and the aromatic aldehyde (52), giving (53) as the predicted product diastereoisomer as part of the enantioselective synthesis of the (S)-chroman-2-carboxaldehyde (54) (Scheme 5.17) [55,56]. The high diastereoselectivity is particularly notable in view of the much smaller effects observed using similar systems [52]. 

SCHEME 14.11. Enantioselective synthesis of highly substituted chromanes by sulfa-Michael-Michael cascade process promoted by aminothiourea thiourea 16. 

HongL, WangL, Sun WS, Wong KY, Wang R (2009) Organocatalytic AsymmetricEnede/-Crafts AUcylation/Cyclization Cascade Reaction of 1-Naphthols and a,P-Unsaturated Aldehydes An Enantioselective Synthesis of Chromanes and Dihydrobenzopyranes. J Org Chem 74 6881... 

SCHEME 5.17 Diasteieo- and enantioselective synthesis of chromanes via organocatalyzed cascade reactions, (a) With a,p-unsaturated aldehyde and (b) with p-y-unsatuiated (J-ketoesters. 

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. 

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 transformation of chroman-4-ones into (S)-chroman-4-ols by Mortierella isabellina has been applied to naphtho[2,3-b]pyran-4-one to provide a synthesis of naturally occurring (S)-4-hydroxy-lapachone (95CJC1399) and various chroman-4-ones have been enantioselectively reduced by NaBTLt in the presence of optically active Co (II) complexes (95AG(E)2145). 

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>. 

The key features of a new total synthesis of vitamin E from 2,3,5-trimethylhydroquinone are an enantioselective Wacker cyclisation which generates the chroman ring system with the... 

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>. 

In order to achieve good enantioselectivity in the Stetter synthesis of chroman-4-ones, it appears that a carbonyl function is necessary in the unsaturated side-chain of the salicylaldehyde-derived starting materials (Scheme 26) <03SL1934>. 

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. ... 

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. 

Tietze and coworkers developed a new total synthesis of vitamin E (1) using a novel enantioselective domino Wacker Heck process as the key step. This allows the formation of the chroman framework 22 with the required i -configuration at the stereogenic center C-2 in 97 % ee with concomitant introduction of part of the vitamin E side chain in 84 % yield. Condensation with (3i )-3,7-dimethyloctanal (21), synthesized from 7 -citronellol (20), followed by reaction with methyl lithium and hydrogenation completed the synthesis. 

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. 

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>. 

Scheme 4.62 Enantioselective intramolecular oxa-Michael reactions for the synthesis of chromanes.

The Wacker oxidation [146], amongst other nucleophilic additions to alkenes, is the most important reaction based on a palladium(II) catalysis. It is also used industrially for the synthesis of acetaldehyde from ethene and water. This oxidative process has been combined with a Mizoroki-Heck reaction by Tietze and coworkers [13] for an enantioselective total synthesis of vitamin E (293) [147] using BOXAX ligand 291 [148]. In this way the chromane ring and parts of the side chain of vitamin E (293) can be introduced in one... 

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]. 

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