Completion of the Total Synthesis

Having retraced the efficient and elegant sequences of reactions that have led to the synthesi of key intermediates 11 and 12, we are now in a position to address their union and the completion of the total synthesis of erythronolide B. Taken together, intermediates 11 and 12 contain all of the carbon atoms of erythronolide B, and although both are available in optically active form of the required absolute configuration, racemic 11 and enantiomerically pure 12... 

The described chemistry leading to the synthesis of key building blocks 16-19 sets the stage for the completion of the total synthesis of both amphotericin B (1) and its aglycon, amphoteronolide B (2). 

With a secure route to pentacyclic amine 2, the completion of the total synthesis of 1 requires only a few functional group manipulations. When a solution of 2 in ethanol is exposed to Pd-C in an atmosphere of hydrogen, the isopropenyl double bond is saturated. When a small quantity of HCI is added to this mixture, the hydro-genolysis of the benzyl ether is accelerated dramatically, giving alcohol 15 in a yield of 96%. Oxidation of the primary alcohol in 15 with an excess of Jones reagent, followed by Fischer esterification, gives ( )-methyl homosecodaphniphyllate [( )-1] in an overall yield of 85 % from 2. 

The completion of the total synthesis only requires a few deprotection steps. It was gratifying to find that the final deprotections could be conducted smoothly and without compromising the newly introduced and potentially labile trisulfide residue. In particular, exposure of intermediate 101 to the action of HF pyridine results in the cleavage of all five triethylsilyl ethers, providing 102 in 90% yield (Scheme 23). Finally, hydrolytic cleavage of the ethylene ketal with aqueous para-toluenesulfonic acid in THF, followed by removal of the FMOC protecting group with diethylamine furnishes calicheamicin y (1) (see Scheme 24). Synthetic calicheami-cin y, produced in this manner, exhibited physical and spectroscopic properties identical to those of an authentic sample. 

Coupling of Key Intermediates and Completion of the Total Synthesis of Zaragozic Acid A/Squalestatin SI... 

With the polycyclic framework of the natural product intact, the completion of the total synthesis only requires a short sequence of reactions. At this juncture, the decision was made to address the problem of reconstituting the A-ring lactone. It was hoped that a selective oxidation of the A-ring allylic ether could be achieved. 

At this point, completion of the total synthesis required removal of the three acetonides and the two silyl protecting groups (Scheme 18). Removal of the silyl groups with TBAF and subsequent treatment to acidic deprotection conditions led to complete deprotection of 110, but failed to provide filipin III. It was sus-... 

Completion of the total synthesis afforded only six further steps, including the installation of the second 2-aminopyrimidine ring via a second domino sequence. This process presumably involves a conjugate addition of guanidine (2-293) to the enone system of2-292, followed by a cyclizing condensation and subsequent aromatization. Under the basic conditions, the ethyl ester moiety is also cleaved and 2-294 is isolated in form of the free acid, in 89 % yield. Finally, decarboxylation and deprotection of the amino functionality yielded the desired natural product 2-295. 

Scheme 24 Final stages and completion of the total synthesis of colombiasin A (36)...

After completion of the total synthesis corresponding experiments could be conducted with methanophenazine (MP) (rac-10), too. To this end, washed... 

The natural product gualamycin, recently obtained from the fermentation broth of a Streptomyces sp., was found to be a potent acaricide [183]. The disaccharide as well as the heterocyclic subunit (101) were synthesized to support the structure proof but the completion of the total synthesis was not reported [184]. 

Vancomycin Vancomycin (57) is an important antibiotic in the treatment of severe bacterial infections by a variety of pathogens and has been one of the most attractive targets for synthetic chemists over the past decade. In 1998, the completion of the total synthesis of the vancomycin aglycon was almost simultaneously reported by Evans [90] and Nicolaou [91]. 

E. COMPLETION OF THE TOTAL SYNTHESIS REDUCTION OF IMINE AND DESULFURIZATION... 

Nicolaou KC, Mitchell HJ, Rodriguez RM, Fyllaktakidou KC, Suzuki H (1999) Total Synthesis of Eveminomicin 13,384-1 - Part 3 Synthesis of the DE Fragment and Completion of the Total Synthesis. Angew Chem Int Ed 38 3345... 

Since (-)-PF1092C (12) has already been transformed into (-)-PF1092A and B (10 and 11) by selective acetylation, die synthesis of 12 constitutes the completion of the total synthesis of 10 and 11 (5). 

Desilylation of 135 afforded alcohol 136, which was oxidized to enal 137 by Parikh-Doering oxidation in 62% yield. Removal of the p-nitrobenzoyl group and the menthyl group resulted in completion of the total synthesis of mniopetal F (6). 

Completion of the total synthesis of clavepictines A and B is shown in Scheme 10. Conversion of 18 to the alcohol 19 via 4 steps and reduction of the hydroxyl group in 19 via iodide gave the quinolizidine 20. Finally, the dienyl moiety was constructed by Julia coupling, and deprotection furnished clavepictine B. Acetylation of the hydroxyl group of clavepictine B gave clavepictine A. 

Total Synthesis of Chasmanine.—Wiesner and his co-workers38,39 have accomplished a landmark in diterpenoid alkaloid chemistry in their completion of the total synthesis of racemic chasmanine (49), a hexacyclic base with six oxygen functionalities. The synthesis of the intermediate (50) was reviewed in the previous Report (Vol. 7, pp. 257—259). 

Scheme 12. Completion of the total synthesis ofwoodrosin I. [a] complex 4 cat., CH2Cl2, reflux, 94% [b] donor 68, TMSOTf cat., Et20, 0°C, 60% [c] hydrazinium acetate, DMF, -10 —> 0°C [d] H2, Pd/C, MeOH, 84% (over both steps).

With the completion of the total synthesis of manzamine C by Nakagawa et al. in 1991 [73], the synthesis and biological evaluation of manzamine C analogs were subsequently reported by the same group [136]. In this study, the azacyclic ring was modified from 11-membered to 5-, 6-, 7-, and 8-membered rings (Scheme 8.19). 

Scheme 16.11 shows the completion of the total synthesis of azaspiracid-1, which followed with slight modifications, the synthesis of the originally proposed structure of azaspiracid-1 (la). This chemistry was also carried out with the corresponding ABCD enantiomer in similar yields. Thns, lithiation of dithiane 51 (n-BuLi n-BnjMg) followed by addition into pentafluorophenol ester 68 resulted in CJ-C27 ketone 69 (50% yield). Ketone 69 was then elaborated into diacetate 70, this time as the TBS ether at C-25, as this protecting group was easier to remove than the acetate used in the earlier work directed toward the original stractnre (see Scheme 16.8). Stille coupling of this allylic acetate (70) then proceeded smoothly, as before, affording the complete Cj-C q backbone 71, which was successfully elaborated to the correct structure of azaspiracid-1 (1), identical in all measured physical properties ( H NMR, C NMR, Rf, [aj ) to the natural material.

Scheme 16.11. The completion of the total synthesis of azaspiracid-1 (Nicolaou 2004a).

After completion of the total synthesis of cardenolides, the main interest in this field has been in structural modifications, undoubtedly as a result of the group s... 

Boger, D L, Honda, T, Total synthesis of bleomycin A2 and related agents. 4. Synthesis of the disaccharide subunit 2-0-(3-0-carbamoyl-a-D-mannopyranosyl)-L-gulopyranose and completion of the total synthesis of bleomycin A2, J. Am. Chem. Soc., 116, 5647-5656, 1994. 

This chapter discusses the complete synthesis of Segment B (5 steps), the final part of the synthesis of Segment C (6 of 9 steps), their combination to building block BC (3 steps), the introduction of Segment A and the completion of the total synthesis of ZK-EPO (1). The synthesis of Segment A (11 steps) is not discussed. 

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