Erythromycin - Synthesis

Synthesis

Over the three decades after the discovery of erythromycin A and its activity as an antimicrobial, many attempts were made to synthesize it in the laboratory. However, the presence of ten stereospecific carbons and several points of distinct substitution has made the total synthesis of erythromycin A a formidable task. Complete syntheses of erythromycins’ related structures and precursors such as 6- deoxyerythronolide B have been accomplished, giving way to possible syntheses of different erythromycins and other macrolide antimicrobials. However, Woodward did successfully complete the synthesis of erythromycin A. This total synthesis begins with (7) and (8). After being coupled, the resulting structure is subjected to a series of reactions, including hydrolysis and stereospecific aldolization. The resulting pure enone is then converted to the desired dithiadecalin product (9) through a series of reduction and oxidation reactions. (9) is then converted to both a ketone (10) and an aldehyde (11).

Figure 1 a)

NaH, THF, Me₂SO; b)AcOH, H₂O; c)MsCL, Py; d)alumina, EtOAc; e)NaBH₄, MeOH; f)MeOCH₂I, KH, THF; g)OsO₄, ether; NaHSO₃, Py(aq); h)Me₂C(OMe)₂, TsOH, CH₂Cl₂; i)CF₃COOH, CH₂Cl₂; j)(CF₃CO)₂O, Me₂SO, CH₂Cl₂; (i-Pr)₂NEt; k)Ra(Ni)-(W-2), EtOH, reflux; l)o-NO₂C₆H₄SeCN, P(n-Bu)₃, THF; m)O₃, MeOH, CH₂Cl₂; Me₂S, NaHCO₃.

With these two species, each of which resembling key segments of the erythronolide A seco acid, an aldol condensation is carried out to yield (12). (12) is put through several reactions, including the addition of benzyl thiol, the coupling of enolates, and stereospecific reduction to yield (13), which contains the carbon skeleton and stereocenters of the erythronolide A seco acid.

Figure 2 a)

Mesityllithium, THF; b)(CF₃CO)₂O, Me₂SO, CH₂Cl₂; (i-Pr)₂NEt; c), KH, HMPA, THF; AcCl; d)NaBH₄, MeOH, CH₂Cl₂; e)MsCl, Py; DMAP, Py, MeOH; f)PhCH₂SH, n-BuLi, THF; g)LAH, ether; h)Ac₂O, DMAP, CH₂Cl₂; i)Ra(Ni)-(W-2), EtOH, DMF, reflux; j)o-NO₂C₆H₄SeCN, P(n- Bu)₃, THF; 30% H₂O₂, THF; k)O₃, MeOH, CH₂Cl₂; Me₂S, NaHCO₃; l)EtCOSCMe₃, LDA, THF; m)t-BuLi, (CH₂NMe₂)₂, THF; AcOH.

(13) is then subjected to a series of reactions including successive deprotections and acetylization to yield (14), a compound that is more likely to yield a lactone. Acetalization of (14) yields a precursor to the desired thioester (15), which was achieved by replacing the terminal methoxy group with the required thio group. (15) is then lactonized in 70% yield to give (16).

Figure 3 a)

Na₂CO₃, MeOH; b)(PhOCH₂CO)₂O, Py, DMAP, CH₂Cl₂; c)MsCl, Py; d)LiOH, 30% H₂O₂, THF; e)LiN₃, HMPA(aq); f)H₂(1 atm), PtO₂, THF; g)ClCOOC₆H₄-p-NO₂, CH₂Cl₂, NaHCO₃(aq); h)NH₂OH⋅HCl, KH₂PO₄, MeOH(aq), reflux; i)Et₃N, CH₂Cl₂; j)mesitaldehyde dimethyl acetal, CF₃COOH, CH₂Cl₂; k)EtSLi, HMPA; l)ClCOS-2-Py, Et₃N, CH₂Cl₂.

To complete the synthesis of erythromycin A, (16) is acylated with p-phenylbenzoyl chloride, undergoes hydrolysis, and is deprotected at its hydroxyl groups at carbons 3 and 5 to yield (17). After a series of glycosidation reactions, (17) is converted to (18). (18) is then subjected to a number of reactions, eventually converting carbon 9 from an amine to the ketone, yielding the final erythromycin A product (1).

Figure 4 a)

BPCOCl, Et₃N, DMAP, CH₂Cl₂; b)NaOH(aq), THF, i-PrOH; c)SiO₂, CF₃COOH(aq), CH₂Cl₂; d)Na- Hg/MeOH; e)N-chlorosuccinimide, Py; f)AgF, HMPA; g)- H₂O.

Total yield for Woodward’s complete synthesis of erythromycin A was approximately 0.02%, leaving future scientists with a clear goal for improvement.