Macrolides enantioselectivity

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

In Ghosh s enantioselective total synthesis of the cytotoxic marine macrolide (+)-amphidinolide T1 (318) [143], the C1-C10 fragment 317 was constructed by CM of subunits 315 and 316 (Scheme 62). The reaction mediated by catalyst C (5 mol%) afforded in the first cycle an inconsequential 1 1 mixture of (E/Z)-isomeric CM products 317 in 60% yield, along with the homodimers of 315 and 316. The self-coupling products were separated by chromatography and exposed to a second metathesis reaction to provide olefins 317 in additional 36% yield [144]. 

The Prelog-Djerassi lactone (abbreviated here as P-D lactone) was originally isolated as a degradation product during structural investigations of antibiotics. Its open-chain equivalent 3 is typical of the methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. The compound serves as a test case for the development of methods of control of stereochemistry in such polymethylated structures. There have been more than 20 different syntheses of P-D lactone.24 We focus here on some of those that provide enantiomerically pure product, as they illustrate several of the methods for enantioselective synthesis.25... 

A short enantioselective synthesis of (-)-(R,R)-pyrenophorin, a naturally occurring anti-fun-gal 16-membered macrolide dilactone, is prepared from (S)-5-nitropentan-2-ol via the Michael addition and Nef reaction (Scheme 4.23).162 The choice of base is important to get the E-alkene in the Michael addition, for other bases give a mixture of E and Z-alkenes. The requisite chiral (S)-5-nitropentan-2-ol is prepared by enantioselective reduction of 5-nitropentan-2-one with baker s yeast.163... 

As an example of the usefulness of the Sharpless asymmetric epoxidation the enantioselective synthesis of (-)-swainsonine and an early note by Nicolaou on the stereocontrolled synthesis of 1, 3, 5...(2n + 1) polyols, undertaken in connection with a programme directed towards the total synthesis of polyene macrolide antibiotics, such as amphotericin B and nystatin Aj, will be discussed. 

Stereocontrolled syntheses of macrolides and macrolactams are well developed. Much remains to be done toward the efficient enantioselective construction of five and suc-membered cyclic ethers and amines. Four recent natural product syntheses illustrate the current state of the art. 

Substituted 5-methylene-l,3-dk>xepines 38 are converted into vinyl acetals 39 by Ni catalysts bearing (R,R)-DuPHOS or (R,R)-ChiraPHOS as chiral ligands (Scheme 11) [16]. Similarly high enantioselectivity can be achieved with 5-methyl-ene-l,3-dioxanes as substrates [17]. Chiral Ru-catalysts are less efficient [18]. Cyclic acetals obtained are an useful starting material for preparation of macrolide antibiotics and other polyketide-derived natural products. 

Rychnovsky and his group have recently developed new synthetic methods that lead to the total syntheses of the polyene macrolides roxaticin [2], roflamycoin [3], and filipin III [4]. The polyol chains of all three natural products were constructed by iterative, stereoselective alkylation of lithiated cyanohydrin acetonides and subsequent reductive decyanation, illustrated here by the synthesis of the polyol framework of filipin III (1) (Scheme I). The bifunctional cyanohydrin acetonide 2, prepared by ruthenium/BINAP catalyzed enantioselective hydrogenation of the corresponding ) -keto ester (BINAP = [ 1,1 -binaphthyl]-2,2 -diylbis(diphenylphosphane)), is deprotonated with LiNEt2 and alkylated with 2-benzyloxy-l-iodoethane. The alkylation product 3 is converted by a Finkelstein reaction into the iodide 4, which is used to alkylate a second... 

Optically active 1,2-diol units are often observed in nature as carbohydrates, macrolides or polyethers, etc. Several excellent asymmetric dihydroxylation reactions of olefins using osmium tetroxide with chiral ligands have been developed to give the optically active 1,2-diol units with high enantioselectivities. However, there still remain some problems, for example, preparation of the optically active anti-1,2-diols and so on. The asymmetric aldol reaction of an enol silyl ether derived from a-benzyloxy thioester with aldehydes was developed in order to introduce two hydroxyl groups simultaneously with stereoselective carbon-carbon bond formation by using the chiral tin(II) Lewis acid. For example, various optically active anti-a,p-dihydroxy thioester derivatives are obtained in good yields with excellent diastereo-... 

It was also shown in the enantioselective synthesis of the macrolide patulolide that the anion of methyl p-tolyl sulfoxide was more reactive towards the imidazolide, prepared from the hemi ethyl sebacate, than the ester group (eq 7). 

Development of diastereoselective and enantioselective aldol reactions has had a profound impact on the synthesis of two important classes of natural products—the macrolide antibiotics and the poly ether ionophores. The aldehyde and the enolate involved in aldol reactions can be chiral, but we shall discuss only the case of chiral enolates. 

The (3-methyl homoallylic alcohol moiety of both anti- and 5yn-configurations is a characteristic structural element of a number of macrolides and polyether antibiotics. Reactions of crotylmetal (2-butenylmetal) reagents with carbonyl substrates provide access to acyclic stereo- and enantioselective syntheses of p-methyl homoallylic alcohols. The alkene moiety of these alcohols can be further elaborated into aldehydes by oxidative cleavage of the double bond, leading to aldol-type products. 

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. 

A convergent, stereocontrolled total synthesis of the microtubule-stabilizing macrolides, epothilones A and B was achieved in the iaboratory of S.J. Danishefsky. During their investigations, they examined several approaches to construct these natural products. One possible strategy to introduce the Cl 5-hydroxyl group in an enantioselective fashion was to use Keck s asymmetric allylation method. Under standard conditions, the reaction provided the desired homoallylic alcohol in good yield and excellent enantioselectivity. 

Thijs, L., Egenberger, D. M., Zwanenburg, B. An enantioselective total synthesis of the macrolide patulolide C. Tetrahedron Lett. 1989, 30, 2153-2156. 

White, J.D., Tiller, T., Ohba, Y, Porter, W.J., Jackson, R.W., Wang, S., and Hanselmann, R., Total synthesis of rutamycin B via Suzuki macrocyclization, J. Chem. Soc., Chem. Commun., 19, 1998. Lafontaine, J.A., Provencal, D.P., Gardelli, C., and Leahy, J.W., The enantioselective total synthesis of the antitumor macrolide natural product rhizoxin D, Tetrahedron Lett., 40, 4145, 1999. 

The aldol reaction is a versatile method for the construction of new carbon-carbon bonds in a regio-, diastereo-, and enantioselective manner. During the last two decades, major progress toward the total synthesis of macrolide antibiotics was made as a result of the development of the stereoselective aldol reaction in acyclic systems. This section is concerned mainly with the boron-mediated aldol reaction, which is particularly effective for the efficient synthesis of P-hydroxy carbonyl compounds [2]. 

Mandelic acid and its derivatives are utilized as convenient precursors for the introduction of a chiral center, and they possess the extra advantage of bearing a useful functional group. Many mandelic acid derivatives also act as chiral auxiliaries for the induction of a chiral center in stereoselective transformations. Numerous natural products, such as macrolides and ionophore antibiotics, possess a carbon framework that may be viewed synthetically as arising from a sequence of highly stereo- and enantioselective aldol condensations. Boron enolates, chiral auxiliaries derived from mandelic acids 1 or 2, provide remarkably high aldol stereoselectivity. 

In recent years, much effort has been spent trying to determine the absolute configuration of the many polyene macrolide asymmetric centers, using well-established enantioselective organic transformations and advanced spectroscopic studies. This work is a necessary prelude to any accurate chemical modification, conformational analysis related to biological activity and, of course, attempt to totally synthesize a given antibiotic or analogue. 

Diastereo- and Enantioselective Aldol Reactions. Optically active 1,2-diol units are widely distributed in natural products such as macrolides, polyethers, and carbohydrates, etc. The aldol reactions of the enolates derived from a-alkoxyacetic acid ester derivatives with aldehydes provide a useful way to construct 1,2-diols, and several as)unmetric reactions have been developed. 

In the enantioselective total synthesis of FD-891, a 16-membered macrolide, the fragment 97 is generated from the aldol reaction between 3-... 

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. 

The catalytic version of this type of reaction was realized by using acetoacetate derived O-silyl dienolate as nucleophiles in the presence of Carreira s catalyst, giving acetoacetate y-adducts in high yields and enantiomeric excesses [119] (Scheme 14.42). The products are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotic and medicinally important HMG-CoA reductase inhibitors. This aldol addition can also be catalyzed by BINOL-Ti complex in the presence of 4A MS with moderate to good enantioselectivity [120]. The same catalyst system was also efficient in the asymmetric aldol reaction between the aldehydes and Chan s diene [ 1,3-bis-(trimethylsilyloxy)-l-methoxy-buta-1,3-diene] and other related silyl enol ethers [121, 122] (Scheme 14.43) or the functionalized silyl enol ether such as 2-(trimethylsilyloxy)furan with good to excellent enantioselectivities [123]. 

The Prelog-Djerassi lactone is a degradation product of the macrolide antibiotics methy my cin and narbomycin. Evans uses it here to illustrate his asymmetric enolate methodology (see section 5.3.2). Of the many syntheses of tnis popular target molecule, this is one of the best in terms of diastereo- and enantioselectivity. 

Enantioselective free-radical reactions of oxazolon-2-ones 99ACR163. Oxazol-5(4//)-ones as intermediates in the formation of macrolides, cyclodep-sipeptides, and cyclopeptides 99JHC1539. 

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