Macrolide epoxidation

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

An alternative disconnection of homopropargylic alcohols substrates for intramolecular hydrosilylation is the opening of an epoxide with an alkynyl anion. This strategy was employed in a total synthesis of the macrolide RK-397 (Scheme 20). Epoxide ring opening serves to establish homopropargylic alcohol C with the appropriate stereochemistry. A hydrosilylation/oxidation protocol affords the diol E after liberation of the terminal alkyne. The... 

However, epoxidations of more rigid unsaturated macrolides have been succesfully achieved in model studies. See, for instance, W.C. Still and A.G. Romero, J. Am. Chem. Soc. 1986,108, 2105 and S.L. Schreiber, T. Sammakia, B. Hulin, and G. Schulte, J. Am. Chem. Soc. 1986, 108, 2106. 

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. 

Oxidation reactions can produce hydroxylation on the aromatic rings, such as in the case of the steroids and thiabendazole, or on the aliphatic carbon chain such as in the case of pentobarbitone. They can also cause epoxidation, which leads to normally unstable intermediates that can be hydrolyzed by epoxide hydrolase to dihydrodiols. In addition, they can produce oxidative dealkylation at the alpha carbons of the alkyl groups attached to a nitrogen, sulfur, or oxygen atom of the drug molecule, as in the case of the macrolide antibiotics and trimethoprim. Moreover, they can induce oxidation of sulfur atoms to the corresponding sulfox-... 

This catalytic epoxidation method has been applied to the synthesis of a variety of natural products, particularly polyhydioxylated compounds, including carbohydrates (54) and macrolides. In addition, this reaction has been used for commercial synthesis of disparlure, a gypsy moth pheromone [J. T. Baker Co. (55) and the Shanghai Institute for Organic Chemistry (56)], and more importantly, glycidol, a versatile intermediate for synthesis of /3-blockers and other functionalized chiral molecules (Arco Co.) (Scheme 23) (57). 

The 16-membered polyfunctionalized antitumor macrolide, epothilone A (118), was synthesized by the Ru-catalysed RCM of 116 to give 117, followed by epoxidation [42-44], The (E) (Z) ratio in 117 may be changed by protecting groups. 

Since such reactivity has recently been reviewed,8 only a few examples are reported here. Acyl halides or epoxides can be alkynylated with preformed silver acetylides. Such processes have been applied to the total synthesis of the antibiotic macrolide (+ )-methynolide,96 and in the total synthesis of the antitumor agent FR901464 isolated from a Pseudomonas species (Scheme 10.62).97... 

In order to optimize the antitumoral properties of radicicol, particularly in vivo, the same group synthesized the analogous cycloproparadicicol, where the epoxide function is replaced by a cyclopropane [64]. Submitted to the conditions of the previous RCM reaction (CH2C12, 42°C, 19h), cydopropyl triene 94 leads to the expected macrolide 95 in only 16% yield, along with 30% of the corresponding 28-membered dimeric macrocycle (Scheme 2.37). After numerous assays, the best conditions tested (toluene, 110 °C, 10 min) brought the yield up to 55%. In this case, the balance between thermodynamic and kinetic factors seems decisive for the course of the reaction. The fact that the monomeric product is predominant at elevated temperature indicates that this form is entropically favored. 

High dilutions reduced the amount of oligomers formed. Preliminary experiments on enantio-enriched hydroxyl esters 20.6 and 20.7, using distannoxane transesterification catalyst, produced stereochemically diverse homo- and heterodimers 20.8-20.10. Functionalization of the macrodiolides was investigated in an effort to create additional structural diversity. Electrophilic epoxidation of macrodiolide 20.9 afforded bis-epoxide 20.11. Further diversification was achieved by treating the macrodiolide bis-epoxide with DBU, which resulted in epoxide ring opening to afford a,P-unsaturated macrolide 20.12. 

Another significant application of the concept of relay deprotection comes from a synthesis of the antitumour macrolides Cryptophycins 1 and 8.644 The penultimate step required a mild method for the introduction of the epoxide ring in the side chain [Scheme 4.340]. A variant of a direct method for the conversion of diols to epoxides developed by Kolb and Sharpless645 was cleverly adapted to the case at hand. Thus diol 340.1 was treated with the 4-azido-1 1,1-tri-methoxybutane in the presence of chlorotrimethylsilane to give the cyclic orthoester 340.2, which decomposed under the reaction conditions with loss of Me SiOMe to give the chlorohydrin ester 3403 (inversion). Selective reduction... 

Modifications other than esterifications have been less extensively reported, although many derivatives have been described in the older literature that were prepared during structure elucidation and basic chemical studies of new macrolides. Some of this work has been compiled in reviews [1, 3, 6, 49], None of these older compounds has been commercially developed. Results from these early studies indicated that antibacterial activity was only minimally affected by epimerization of the C-9 substituent, alkylation of the 9-hydroxyl group, saturation of the C-10,11,12,13-diene, or epoxidation of the C-12,13 double bond [26, 49-52]. The aglycone of niddamycin (11a) Figure 5.4) was recently transformed into a series of 9-a-and 9-j8-A, iV-dialkylamino-9-deoxo-10,11,12,13-tetrahydro derivatives the 9-a-N,iV-dimethylamino analogue (A-65352) (11c) exhibited activity comparable to josamycin in vitro and in vivo [53]. The 9-a-N,N-dimethylamino derivative of niddamycin itself (A-75835) (lib) was subsequently reported to be more active than josamycin [54]. 

Erythromycin can cause acute carbamazepine intoxication, probably by inhibiting its hepatic metabolism (63). Erythromycin may also directly inhibit the conversion of carbamazepine to its epoxide. In a controlled study of the effects of eiythromycin on carbamazepine pharmacokinetics in healthy volunteers, the clearance of a single dose of carbamazepine was reduced by 19% during erythromycin treatment (64). In contrast, the single-dose pharmacokinetics of phenytoin were not affected by erythromycin (65,66). After withdrawal of the macrolide, carbamazepine concentrations quickly return to normal (67). If co-administration of erythromycin and carbamazepine cannot be avoided, a dosage reduction of... 

As shown below, the attack of epoxide 6 with lithium dimethylcuprate is a key step of Hanessian et al. s erythronolide synthesis [23]. This methodology was also applied to the preparation of other polyketide-derived macrolides. Specific to erythronolide, introduction of the methyl group at C2 was achieved according to Scheme 11.3. 

Another example from the macrolide field is the synthesis of antimycin A3, which starts with opening of epoxide 9 [28]. Opening of this manno epoxide with butylmagnesium chloride afforded the C3 branched-derivative 10 with total regio- and stereo-selectivity. Again the Fiirst-Plattner rule applies and the introduction of the substituent at C3 was expected. The remainder of the synthesis... 

Alcohols resulting from a first epoxide opening can indeed be submitted to a second sequence, as shown in Procter s approach to the macrolide antibiotic rosaramycin [36]. Here again the 1,6-anhydro bridge was chosen to lock the epoxides in the proper conformation to ensure completely regioselective introduction of an allyl chain at C2 in 28 (Scheme 11.9). Going back to the usual... 

Combined uses of epoxide opening and the above-mentioned sequence involving ketone formation, Wittig methylenation and reduction was exploited by Lukacs to produce all possible stereoisomers of methyl 2,4-dideoxy-2,4-dimethyl hexopyranosides (key compounds of macrolide antibiotics syntheses). The sequence, illustrated in Scheme 11.25, utilized the altro derivative 7, which was transformed into a 3 1 mixture of 104 and 105 via olefin 103. 

Structure-activity relationship studies indicate that the intact macrolide ring, the epoxide group, the chloro and O-methyl groups in unit B, and the methyl group in unit C are essential for the in vivo activity of cryptophycin 1 (Fig. 51) ... 

The spongistatins are a family of architecturally complex bisspiroketal macrolides, which display extraordinary cytotoxicity. During the second generation synthesis of the ABCD subunit of spongistatin 1, A.B. Smith and coworkers utilized the Keck allylation to construct the Kishi epoxide. The allylation was carried out under standard conditions, using tributyl-(2-ethylallyl)-stannane as the allylstannane reactant. The desired product was formed in high yield and a diastereomeric ratio greater than 10 1. 

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