Prelog-Djerassi-lactone

The Prelog-Djerassi lactone (abbreviated as P-D-lactone) was originally isolated as a degradation product during structural investigation of antibiotics. Its open-chain precursor 1, is typical of methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. 

There have been more than 20 different syntheses of P-D-lactone.132 We will focus here on some of those which provide enantiomerically pure product, since they illustrate several of the methods for enantioselective synthesis.133 

The stereochemistry of the C-3 hydroxyl is established in step E. The Baeyer-Villiger oxidation proceeds with retention of configuration of the migrating group (see Section 

so the correct stereochemistry is established for the C—O bond. The final center for which configuration must be established is the methyl group at C-6. The methyl group is introduced by an enolate alkylation in step F, but this reaction is not highly stereoselective. However, because this center is adjacent to the lactone carbonyl, it can be epimerized through the enolate. The enolate is formed and quenched with acid. The kinetically preferred protonation from the axial direction provides the correct stereochemistry at C-6. 

In step D, a chiral auxiliary, also derived from cysteine, is used to achieve double stereodifferentiation in an aldol condensation. A tin enolate was used. The stereoselectivity of this reaction parallels that of aldol condensations carried out with lithium or zinc enolates. Once the configuration of all the centers has been established, the synthesis proceeds to P-D-lactone by functional group modifications. 

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 

25 For other syntheses of enantiomerically pure Prelog-Djerassi lactone, see F. E. Ziegler, A. Kneisley, J. K. Thottathil, and R. T. Wester, J. Am. Chem. Soc., 110, 5434 (1988) A. Nakano, S. Takimoto, J. Inanaga, T. Katsuki, S. Ouchida, K. Inoue, M. Aiga, N. Okukado, and M. Yamaguchi, Chem. Lett., 1019 (1979) K. Suzuki, K. Tomooko, T. Matsumoto, E. Katayama, and G. Tsuchihashi, Tetrahedron 

The adduct cyclized to a lactol mixture that was oxidized by TPAP-NMMO to give the corresponding lactones in an 8 1 ratio (86% yield). Hydrolysis in the presence of H202 gave the P-D lactone and recovered chiral auxiliary. 

Hashimoto, Y. Hagiwara, M. Ochai, and E. Fujita, J. Chem. Soc., Chem. Commun. 1985 1419. 

The stereochemistry at C-4 and C-6 is then established. The cuprate addition in step C, occurs anti to the substituent at C-2 of the p3o an ring. After a Wittig methylenation, the catalytic hydrogenation in step D, establishes the stereochemistry at C-6. 

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. 

The chiral auxiliary is the oxazolidinone (24) derived from IS,2R) norephedrine. Acylation with propionyl chloride gives (25) and this is deprotonated to afford exclusively the internally chelated Z-enolate, which reacts with methallyl iodide from the face opposite the methyl and phenyl groups of the auxiliary. The product (26), a 97 3 mixture of diastereomers, is purified to a ratio of better than 500 1. Reductive removal of the auxiliary and careful oxidation of the primary alcohol under non-racemising conditions affords the chiral (5)-aldehyde (27). This in turn is reacted with the boron enolate of (25), which furnishes with remarkable selectivity the u aldol product (28). The reason for the choice of boron rather than lithium is to invert the facial selectivity of the reaction— the enolate is no longer constrained to be planar by internal chelation and rotates in order to place the bulky dibutyl borinyl group on the opposite side to the methyl and phenyl  

The aldehyde now attacks from the less-hindered side of the enolate, again opposite the substituents of the auxiliary, via the Zimmerman-Traxler six-membered cyclic transition state  

Note that the natural tendency of the aldehyde to undergo nucleophilic attack according to Cram s rule is overridden. The selectivity of this reaction surprised even the authors, who found the product was a400 1 mixture of u and / diastereomers at the two newly created stereogenic centres, with an overall asymmetric induction with respect to the chiral auxiliary of no less than 660 1. 

After hydroxyl protection, the remaining stereogenic centre is installed by hydroboration with the bulky t-hexyl borane, which proceeds with a modest but useful 1,3-diastereoselectivity of 85 15. Finally, the terminal hydroxyl group is oxidised to the acid, and the chiral auxiliary removed with base. The final product was crystallised to a diastereomeric and enantiomeric purity of better than 99.9%. 

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Scheme 13.34. Prelog-Djerassi Lactone Synthesis P. A. Grieco and Co-Workersa...

Scheme 13.35. Prelog-Djerassi Lactone Synthesis W. C. Still and K. R. Shawa...

Scheme 13.36. Prelog-Djerassi Lactone Synthesis S. Masamune and Co-Workers3...

Scheme 13.38. Prelog-Djerassi Lactone Synthesis Y. Nagao and Co-Workers5... 

Scheme 13.43. Prelog-Djerassi Lactone Synthesis N. Kawauchi and H. Hashimoto ...

Scheme 13.44. Prelog-Djerassi Lactone Synthesis R. E. Ireland and J. P. Daub3...

Scheme 13.49. Prelog-Djerassi Lactone Synthesis J. Cossy, D. Bauer, and V. Bellosta8...

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

Acetalization of oxo aldehydes is used to protect sensitive aldehyde products, especially in asymmetric hydroformylation preventing racemization of an a-chiral aldehyde product [18-22,27]. Acetal formation can also be applied to the synthesis of monocyclic or spirocyclic pyranes as potential precursors and building blocks for natural products such as pheromones or antibiotics. A representative example is the synthesis of the pyranone subunit of the Prelog-Djerassi lactone. For this purpose, various 1,2-disubstituted homoal-lylic alcohols were used (Scheme 3) [32],... 

As a model study for this methodology, Evans and Bartroli carried out the synthesis of (+)-Prelog-Djerassi Lactonic acid 47 [14b] [27], which is a degradation product of either methymycin or narbomycin [28] and has some of the important structural features present in macrolide antibiotics. 

Note that aldol condensations I, II and III concern the creation of a relative configuration 2,3-syn, which can be easily achieved starting from the (Z)-enolates 74a-74c. Scheme 9.27 summarises the synthesis of 93 and 95, which are equivalent to fragments B and A, respectively. Compound 88 is the abovementioned Prelog-Djerassi lactonic acid 42 which is obtained in optically pure from (>98% ee). On the other hand, for the stereochemical control of the aldol condensation IV a different methodology is necessary whih involves the coupling of two structurally predefined reactants and which will not be discussed here (Scheme 9.28). An important feature of this reaction is that the coordination of Li" " with the oxygen atom at the P-position of the aldehyde 95 is mainly responsible for the observed stereoselection [22e]. 

Common substructural motifs in polyketide natural products are six-membered ring lactones, lactols, and tetrahydropyrans. It was recognized by Wuts and co-workers that hydroformylation of readily available homoaUyhc alcohols would provide a direct and efficient entry into these ring systems. Such an approach was employed in a synthesis of Prelog-Djerassi lactone (Scheme 5.11) [13]. 

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