Stereoselective synthesis macrolide antibiotics

Using FmA catalysis and protected 4-hydroxybutanal, compound (97) has been stereoselectively prepared as a synthetic equivalent to the C-3-C-9 fragment of (-F)-aspicillin, a lichen macrolactone (Figure 10.35) [160]. Similarly, FruA mediated stereoselective addition of (25) to a suitably crafted aldehyde precursor (98) served as the key step in the synthesis of the noncarbohydrate , skipped polyol C-9-C-16 chain fragment (99) of the macrolide antibiotic pentamycin [161,162]. 

Figure 10.35 Stereoselective generation of chiral precursors for the synthesis of the lichen macrolactone (+)-aspicillin and the macrolide antibiotic pentamycin using FruA catalysis.

Andrew Regan was born in Rawtenstall, Lancashire and studied at the University of Cambridge, where he obtained his BA in 1981 (MA 1985), and his PhD in 1984, under the supervision of Professor Jim Staunton. From 1984-1985 he held an SERC-NATO Research Fellowship at Columbia University in the laboratories of Professor Gilbert Stork. He returned to the UK in 1985 to a lectureship in organic chemistry at the University of Kent at Canterbury, and since 1990 has been a lecturer in the Department of Chemistry at the University of Manchester. His research interests include the synthesis of phosphinic-acid hormone mimics, simplified macrolide antibiotics and anti-tumour compounds, stereoselective methodology, and the use of enzymes in synthesis. 

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). " ... 

Nakajima, N., Tanaka, T, Hamada, T, Oikawa, Y, and Yonemitsu, O., Highly stereoselective total synthesis of pikronolide, the aglicon of the first macrolide antibiotic pikromycin. Crucial role of benzyl-type protecting groups removable by 2,4-dichloro-5,6-dicyanobenzoquinone oxidation, Chem. Pharm. Bull., 35, 2228, 1987. 

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. 

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]. 

A number of new macrolide antibiotics with interesting bioactivity have been isolated, and the unique and complex structures have been determined. Toward the total synthesis of such attractive macrolide antibiotics, very efficient synthetic strategies and useful methodologies have been developed. Recent advances in macrolide synthesis based on newly developed strategies and methodologies are remarkable various complex macrolides having many chiral centers have been efficiently synthesized with excellent stereoselectivity. Recently, combinatorial... 

The field of organic synthesis has seen equally rapid advances. The emphasis has been in the development of new stereoselective methods for achieving specific synthetic transformations. The exciting synthetic approaches in the field of macrolide antibiotics, anti-tumor agents and other biologically important natural products serve to exemplify these developments. 

Thomas et al. [90] prepared two 17-membered macrocyclic tetraenes that are possible precursors of the natural product lankacidin C in this case, a trisubstituted vinyl iodide was involved, and the amount of Pdjdbaj required was relatively high (30%). Toshima et al. [91] reported a highly stereoselective total synthesis of the macrolide antibiotic concanamycin F again, intermolecular and intramolecular vinyl-vinyl couphngs were used. WhUe liCl was used as an additive in the former, it was replaced by DIPEA in the latter. In a recent pubUcation [49], Toshima et al. 

Similarly, the hydroformylation of 2-phenyl-4-(prop-2-enyl)- 1,3-dioxane 73 affords an all-anti-stereotriad 75 which becomes a valuable intermediate in the total synthesis of the macrolide antibiotic bafilomycin A [51] (Figure 22). The conformation for intermediate 74 was calculated to be the most stable and the equatorial methyl group appears to cause the high stereocontrol observed. As can be deduced from these representative examples six-member rings seem to provide good stereoselectivities. 

Studies on the stereochemical outcome of the reaction of 2-alkenyl organometallic reagents with aldehydes have increased recently, largely because stereoselectively produced homoallylic alcohols are synthetically equivalent, by cleavage at the carbon-carbon double bond, to the type of aldol adduct stereoisomers required for macrolide antibiotic total synthesis. A new stereoselective synthesis of (Z)-2-alkenyltins (46a) or the corresponding silanes (46b) from allyl or vinyl 9-BBN derivatives has appeared (Scheme 20). The... 

The topic of the stereoselectivity of aldol condensation reactions has received much attention recently owing to efforts directed toward the total synthesis of macrolide antibiotics. The carbon backbone of many of these substances may be viewed as capable of being derived by combinations of several aldol additions. Because of the number of chiral centers, it is necessary that a high level of stereochemical control be achieved in the carbon-carbon bond-forming steps. Hence, a number of fundamental studies have been concerned with stereoselection in aldol addition reactions. 

In special cases, the desired regio- or stereoselectivity can be achieved with the help of the internal regio- or stereocontrol exerted by a moiety incorporated into a proper position of the substrate. During the synthesis of a key building block of the macrolide antibiotic bafilomycin Ai, the spatial shielding of one face of the double bond by the equatorial methyl group proved to result in the exclusive formation of the all-anti stereotriade aldehyde 9 [16]. 

Accordingly, the Evans protocol, when applied to A-propionyl oxazolidinone 51 derived from ephedrine, leads to the predominant formation of the diastere-omeric syw-aldols, again with outstanding stereoselectivity. In this case, the enolate attacks the Re-hce of aldehydes with high preference. The procedure is illustrated in Scheme 4.48 for an aldol addition to a-benzyloxyacetaldehyde yielding the crude product 213 in a diastereomeric ratio of higher than 99 1. After recrystallization, the stereochemically homogeneous aldol adduct 213 was transformed into the Weinreb amide 214 in the course of a total synthesis of the macrolide antibiotic cytovaricin. In the transamination step, the chiral auxiliary 46 was recovered [111]. 

C9 fragment of the lichen marcolactone (+)-aspicillin [143]. A FraA-mediated stereoselective addition also served as the key step in the synthesis of the noncarbohydrate, skipped polyol C9-C16 fragment 82 of the macrolide antibiotic pentamycin [144,145],... 

Miyashita, M. and Tanino, K. (2004) Natural product synthesis based on new acyclic stereocontrol. Stereoselective total syntheses of zincophorin, the ionophore antibiotic, and scytnphydn C, an antitumor marine macrolide./. Synth. Org. Chem. Japan, 62,1080-1094. 

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