Chiral ortho ester

The enantioselective total synthesis of the 13-membered macrolide fungal metabolite (+)-brefeldin A was accomplished using a triple chirality transfer process and intramolecular nitrile oxide cycloaddition in the laboratory of D. Kim. To set the correct stereochemistry at C9, the stereoselective ortho ester Claisen rearrangement was applied on a chiral allylic alcohol precursor. The rearrangement was catalyzed by phenol and it took place at 125 °C in triethyl orthoacetate to give 84% isolated yield of the desired diester. 

Inverse demand cycloaddition of isoquinolinium salt 1 to chiral enol ethers, acetals and ortho esters 2 gives diastereomeric tetralins 3 and 4 with the diastereoselectivity depending on the nature of the dienophile and on the chiral auxiliary1. The primary tricyclic adduct solvolyzes to the tetralinaldehyde acetal in acidified alcohol. 

Optically active allylic alcohol 3, prepared from propargylic alcohol 2, is rearranged by the ortho ester variation to 4 with >96% chirality transfer and cyclized to lactone 5377-378. 

A double Claiscn ortho ester sequence is used to convert the chirality of glyceraldehyde via 7 to cyclopentanone 8305. 

In 5,6 rearrangements with only the double bond of the allylic moiety as part of a ring, chirality is transferred from an acyclic side chain to the ring system. Complete chirality transfer is observed in the ortho ester rearrangement of (R)-alcohol 1, obtained in optically active form by microbiological reduction, to (R)-ester 2393. 

Quaternary stereogenic centers / to C-6 do not exhibit a significant chiral induction. The simple Claisen rearrangement of cyclohexanone acetal 1 with butyl vinyl ether in the presence of mercury(II) acetate at 175 °C results in a 45 55 diastereomeric mixture of products 2. The ortho ester variation gives a similar result631. 

The concept of enantioconvergent synthesis has heretofore been virtually restricted to cases in which the chiral center is directly epimerizable such as in a-amino acids. In an alternative view, the separate transformation of two enantiomers via stereochemical 1y complementary pathways into a single enantiomeric series represents a case of enantioconvergence.(D For example, conversion of the enantiomeric alcohols la and lb to Ic via the Z and olefins respectively converge to the same enantiomer of the product derived via a Claisen ortho ester rearrangement (equation 1). (, 3)... 

Dialkoxyboronic esters are a priori very weak Lewis acids. Diels-Alder reaction of an ortko-boronoanilide dienophile with cyclopentadiene proceeds faster than both its para isomer and the unsubstituted derivative, thereby confirming that self-activation by internal coordination is operative with ortHo-boronoanilide (Equation 32 vs. 33). However, the level of 1,8-stereoselection observed in the Diels-Alder reaction of chiral boronic ester derivatives is only minimal (up to 18% de) [31],... 

Clayden s group has reported pioneering studies on asymmetric ortho-lithiation reactions. They have shown that treatment of lithiated hindered tertiary amides such as 19 with chiral sulfinate esters of type 20 gives the... 

High levels of chirality transfer have been observed in ortho ester Claisen rearrangements. Treatment of (2/ ,3E)-3-penten-2-ol with ethyl orthoacetate gave the ethyl ester of (3/ ,4 )-3-methyl-4-hexenoic acid in 90% optical yield.The... 

Zhou Y-G, Tang W, Wang W-B, Li W, Zhang X. Highly effective chiral ortho-substituted BINAPO ligands (o-BINAPO) applications in Ru-catalyzed asymmetric hydrogenations of p-aryl-substituted p-(acylamino)acrylates and P-keto esters. J. Am. Chem. Soc. 2002 124(18) 4952-4953. 

However, the decarboxylation reaction predominates when the ortho- and para-positions of the aromatic ring are blocked by alkyl substituents [62]. Recently, Inoue and coworkers have studied the photodecarboxylation of chiral aryl esters accommodated in CD and polyethylene films [63-67]. In the photolysis of 2,4,6-trimethylphenyl-2-methylbutyrate 19, two reaction pathways simultaneously open to afford alkylmesitylene 20 and 2,4,6-trimethylphenol 21, respectively (Scheme 11). The yields of 20 and 21 obtained in aqueous and y-CD solutions are much lower (0-11%) than those in organic solution, which is ascribed to the intermolecular reaction between CD and 19. The j6-CD-mediated photodecarboxylation of racemic 19 furnishes the (7 )-enantiomer of 20 in up to 14% ee, suggesting that the reaction pathway differs in the presence and absence of j6-CD and one of the enantiomers of 19 reacts faster than another in the j6-CD cavity. When the photoreaction is carried out in the presence of y-CD, only a very small amount of... 

Only one example, showing high stereoselectivity, is known in this class of reactions. On treatment of the acyclic glycine cation equivalent 1 (see Appendix), containing the ( + )-cam-phor-10-sulfonamide ester as a chiral auxiliary, with boron trifluoridc and anisole at 0"C a mixture of aromatic substitution products is obtained in essentially quantitative yield 55. Besides 11 % of cuV/io-substitution product, the mixture contains (R,S)-2 and its (/ ,/ )-epimer in a ratio >96 4 (NMR). The same stereoisomer 2 predominates when the reaction is conducted in sulfuric acid/acetic acid 1 9, although the selectivity is slightly lower (91 9 besides 25% of ortho substitution). 

In a closely related study, Tung and Sun discussed the microwave-assisted liquid-phase synthesis of chiral quinoxalines [80], Various L-a-amino acid methyl ester hydrochlorides were coupled to MeOPEG-bound ortho-fluoronitrobenzene by the aforementioned ipso-fluoro displacement method. Reduction under microwave irradiation resulted in spontaneous synchronous intramolecular cyclization to the corresponding l,2,3,4-tetrahydroquinoxalin-2-ones (Scheme 7.71). Retention of the chiral moiety could not be monitored during the reaction, but after release of the desired products it was found that about 10% of the product had undergone racemization. 

Chiral /3,/3-diaryIpropionic acid moieties are often found in compounds showing biological activities, such as antiarrhythmics vasodilators antidepressives " , antihistamines and controllers of cerebral insufficiency ". In the course of synthetic studies of chiral -diaryIpropionic acid derivatives, Merck researchers developed stereoselective conjugate addition of aryllithium reagents to the a,/ -unsaturated fert-butyl esters 18 bearing a chiral imidazolidine or oxazolidine auxiliary at the ortho position of an aryl group. The addition furnished chiral -diaryIpropionic acid derivatives 19 with... 

Planar chiral arene Cr(CO)3 complexes have been shown to undergo highly diastereoselective cycloadditions and Kiindig has extended this protocol to the [3+2] cycloadditions of azomethine ylides (96). Enantiopure ortho- substituted p -benzaldehyde complex 337 underwent condensation with an ot-amino ester to afford imine 338 in the presence of EtaN. Subsequent treatment with methyl acrylate at ambient temperamre in the presence of LiBr and EtaN delivered cycloadduct 339, with excellent stereoinduction and high material yield. Photoinduced oxidative decomplexation in air furnished the final arylpyrrolidines (Scheme 3.114). 

Tomioka et al. reported the asymmetric Michael addition of lithium thiolates catalyzed by chiral aminoether 31 (Scheme 8D. 18) [39]. Thus, in the presence of catalytic amounts of 31 (10 mol %) and lithium 2-(trimethylsilyl)thiophenolate 32-Li (8 mol %), thiol 32 (3 equiv.) reacted with a,p-unsaturated esters at -78°C in toluene-hexane solvent to give the Michael adduct with up to 97% ee. In the ahsence of 31, the reaction of thiophenol proceeded in only 0.5% yield at room temperature. A monomeric complex consisting of 31 and lithium is proposed as the key reactive species in this asymmetric reaction. The trimethylsilyl group at the ortho-po-sition of the thiol moiety in 32 contributes to the formation of the stereochemically defined monomeric chelated structure, wherein the lithium cation is coordinated with the three heteroatoms of the tridentate ligand 31. The reactions of acyclic /nmv-a,P-unsaturated esters (R1 = Me, Et, Pr, Bu, Bu, PhCH9 R2 = H) proceeds with high enantioselectivity in... 

The optically pure bis-naphthalene ortho-methoxy amide 117 cyclized to the l,4-diazepin-5-one 118 in 86% yield and with >95% ee upon refluxing in ethylenediamine for 5 h to provide the first axially chiral 1,4-diazepine derivative (Scheme 64) <2000SL1616>. This example of a type g ring closure in which the leaving group is MeOH, proceeded in lower yield with an ot/ o-hydroxy substituent, with product distribution largely redirected toward an imidazolidine derivative in which the ethylenediamine reacted solely with the ester. In the structurally simpler salicylic acid ester series, activation of the phenol as the trifluoromethanesulfonate facilitated the SnAr reaction <1995TL7595>. 

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