Synthesis of Macrolides

A simple possibility for the synthesis of esters, the reaction of an acid chloride with an alcohol, was used by Schrage and Vogtle [58] for a two-step synthesis of the macrocycle 63 from the alcohol 61 and the acid chloride 62. Compound 63, an example from the field of host/guest chemistry, forms a cavity, as studied with CPK-models, which could include planar, aromatic guests. Crystals obtained from benzene/ -heptane point to a 1 2 stoichiometry of 63 and benzene according to NMR-spectroscopic data. However, whether this is a molecular inclusion complex or just a clathrate is not yet known. 

Another synthetic strategy known from peptide chemistry consists in the transformation of an acid into an activated ester and its subsequent reaction with an alcohol. An example of this strategy is the preparation of the 32-membered macrolide tetranactine 65 from the acid 64 which is activated by 3-cyano-4,6-dimethylpyridine-2-thiol 66 [59]. 

Another example of the activation of a hydroxy acid was described by Rastetter and Phillion [60] First the 0-protected hydroxyacid 68 reacts with a thiol group containing crown ether 67. Then the resulting thioester 69 reacts with potassium mrt-butoxide to give the alkoxide. At the same time a complexation of the potassium ion by the [18]crown-6 part of the molecule occurs. Thus, the alkoxide ion comes close to the carbonyl group of the molecule, so that nucleophilic attack leading to ring formation is facilitated (cooperation of dilution principle, template effect, and ion pair interaction). 

Regarding the temperature dependence of the formation of oligomers in the macrolide synthesis under Yamaguchis conditions for macrocycles, Seebach et al. 

An alternative ester synthesis, the reaction of a carboxylate anion with an alkyl halide, was used by Madejewski [62] for the preparation of ( , )-l,9-dioxacy-clohexadeca-3,1 l-dien-2,10-dione (76) under dilution conditions. This 16-membe-red dilactone represents a precursor for the synthetic norpyrenophorin 77 a, the physiological activity of which corresponds to the one of the natural products pyrenophorin 77b and vermiculin 77c. The lactone 76 can be obtained in 77% yield by dimerization of ( )-7-bromo-2-heptenic acid (75) in DMF in the presence of potassium carbonate. 

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Total synthesis of macrolide immunodepressants using 1,3-dithiane aldol couplings and a-bond olefin constructions 98ACR35. 

Available methods for the synthesis of macrolides involve the cyclization of long-chain bifunctional precursors,3 depolymerization processes,4 ring-enlargement reactions,5 and special methods... 

At the start of the analysis when you have done no more than recognise the FGs and note special features (such as rings) or easy disconnections, note also the number of chiral centres and their relationship to each other. The Prelog-Djerassi lactone 1 is an important intermediate in the synthesis of macrolide antibiotics.1 It has a six-membered lactone ring and a separate carboxylic acid. More to the point, it has four chiral centres la. Three (1-3) are adjacent and one (5) separate. We might say that the three adjacent centres should be easy to control because they are next to each other but that we might have trouble with C-5. Another way to look at it is to say that the three round the six-membered ring (2, 3 and 5) should be easy to control, as the... 

This use of 1 as a carbonyl synthon has been extended to a synthesis of macrolides by use of a long-chain alcohol for the acylation step, followed by Pd(0)-catalyzed cyclization and deblocking (equation II). 

A recent example for this strategy is the combinatorial synthesis of macrolide analogues based on Erythromycin A by Akritopoulou-Zanze et al. which is outlined below [14]. 

The first chapter focuses on the total synthesis of macrolide-based microtubules stabilizing agents and on SAR data thereof, which have not been covered in other... 

Highly stereocontrolled synthesis of 2,6-dideoxy sugars and its use in the synthesis of macrolide antibiotics 92YGK303. 

Total synthesis of macrolide and ionophore antibiotics containing fragments of tetronic acid 92YZ358. 

The asymmetric approaches include the preparation of the configurationally stable chiral aUenyltin starting from enantio-enriched propargyUc precursors. When submitted to transmetaUation with Sn, Bi or In Lewis acids before addition to the aldehyde, the homopropargyl alcohol is obtained in a 95 5 anti/syn ratio and in a 90% ee . On the other hand, the use of a chiral aUenyltin reagent, without prior transmetaUation, gives the syn adduct selectively (95 5) (equation 12) . However, the use of chiral aUenyltin and chiral aldehydes may lead to the same match/mismatch effect that was observed with allyltins . Both approaches were applied to the synthesis of macrolides subunits ° i . 

Di-t-butylthioketene (266), while unreactive on excitation to the S, state, undergoes reaction via the thiirenylidene carbene (267) and zwitterionic intermediates on excitation to the S2 state the products of irradiation in methanol, for example, include the thiirane (268) and the thio-ester (269). The photofragmentation of phenacyl sulphides to thiones has been employed in a synthesis of macrolides. ... 

TTie oxidative cleavage of 7-stannyl alcohols will be discussed in Volume 7, Chapter 4.2. Two recent examples of this so-called oxidative fragmentation should be given. Posner has described a flexible and simple synthesis of macrolides involving this reaction to produce both ring enlargement and regio-... 

As noted in the discussion of ( )-selective alkene formation, Kishi has found that a-substituted aldehydes reacted with trimethylphosphonopropionate and KOBu to produce the (Z)-alkene selectively. A strongly dissociating base is critical to this approach. In addition to the examples already presented in the discussion of ( )-alkene formation, the (Z)-selective reaction has recently been applied to the synthesis of macrolide antibiotics. In this example, a trisubstituted alkene was formed and closed to the lactone (148 equation 33). In an application to diterpenoids. Piers encountered an example of how substrate-specific the alkene formation can be. With a-dimethoxyphosphonyl-y-butyrolactone (150), the reactions with simple aldehydes proceeded with very high selectivity [(Z) ( ) = 99 1]. On application of the reaction to the more complex aldehyde (149) the (Z) ( ) stereoselectivity dropped to 3 1 in 58% yield (equation 34). No selectivity was observed on reaction with benzaldehyde. Although for hindered substrates, strongly basic conditions with a dimethyl phosphonate can be a simple and effective method for the synthesis of (Z)-isomers, the reaction is not general. In 1983, Still and coworkers introduced methodology that used bis(trifluoroethyl)phosphonoesters (153) to provide a facile approach to (Z)-aIkenes (154) when reacted with aldehydes (equation 35). " ... 

Paterson, I., Mansuri, M. M. Recent developments in the total synthesis of macrolide antibiotics. Tetrahedron 1985,41, 3569-3624. 

Nakata, T. Total synthesis of macrolides. Macrolide Antibiotics (2nd Edition) 2002,181-284. 

Lactone ring expansion. The lithio derivative from this sulfoxide (LDA) reacts with lactones to form adducts which on further treatment with KH and then r-BuLi are transformed into ketenes. Acidification regenerates lactones of one size larger. This reaction sequence works well for expansion of 5- and 6-membered lactones. For the synthesis of macrolides, it is necessary to quench the ketene with pyridine-2-thiol and use the Corey-Nicolaou method to effect reclosure of the lactone ring. 

Section 4 deals with the total synthesis of macrolides having more than one lactone linkage in the macrocyclic ring. Compounds included in this group range from the dimeric lactone pyrenophorin and the trichothecanes to the tetrameric lactone nonactin. 

A unique asynunetric isomerization of 2-substituted 5-methylene-l,3-diox-anes 22 to 5-methyl-4H-l,3-dioxins 23 was catalyzed by a ruthenium complex of DIOP under a hydrogen atmosphere (Scheme 3). Although the enantiomeric purity remained in the range of 35 to 50%, cyclic acetals obtained are promising starting materials for the synthesis of macrolide antibiotics and other polyketide-derived natural products [30]. 

Kimura, Y., and S. L. Regen, High Dilution via Solid-Liquid Phase Transfer Catalysis A Practical Approach to the Synthesis of Macrolides, /. Org. Ghem., 48,1533 (1983b). 

Finally, a recent noteworthy development is the use of molecular mechanics calculations to rationalize and predict the stereoselective reduction of large-ring ketones. This has been of particular interest to chemists working on the synthesis of macrolide antibiotics. An example is the reduction of the cyclic oxolactone 3-methyl-2-oxa-l,7-cyclotetradecanedione with LS-Se-leetride or L-Selectride to give the /ram-alcohol with d.r. (transjcis) 90 10131. 

At the start of the analysis when you have done no more than recognise the FGs and note special features or easy disconnections, note also the number of chiral centres and their position. The Prelog-Djerassi lactone (1) is an important intermediate in the synthesis of macrolide antibiotics. It has a lactone ring, a carboxylic acid, and four chiral centres—three adjacent C2-C4) and one (C6) separate. 

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]. 

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