Y. Ishihara Erythronolide and Erythromycin Baran Lab GM OH 6 O Me. propionyl CoA. mycarose glycosyl

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1 Y. Ishihara Erythronolide and Erythromycin aran Lab GM propionyl Co 0 methylmalonyl Co ( equiv.), polyketide synthase, β-ketoacyl reductase, β-ketoacyl dehydratase enzyme-bound -deoxyerythronolide seco acid (linear heptaketide) cyclization upon cleavage from polyketide synthase -deoxyerythronolide [] at C and C cytochrome P0 (C hydroxylase) erythronolide [] at C erythronolide mycarose desosamine mycarose desosamine erythromycin C (JC,, 0) erythromycin D (JC,, 0) [] at C -methyl bsolute configuration of erythromycin was first established via X-ray analysis in Tetrahedron Lett.,,. -methyl erythromycin (JC,, 00) erythromycin (JC,, 0) [] at C erythromycin E (Tet.,, ) erythromycin F (J. ntibiot.,, ) erythromycin G (J. ntibiot. 00,, 0) erythronolide erythronolide I (rg. Lett. 00,, )

2 Y. Ishihara Erythronolide and Erythromycin aran Lab GM erythromycin erythromycin : - Currently used as an antiobiotic agent; especially useful for patients with penicillin allergies. - Isolation first reported in U.. Patent,, by R. L. unch and J. M. McGuire (Eli Lilly), filed in and approved in ; originally called "erythromycin". - Quotes from the patent: "[...] the empirical formula of erythromycin [is] C - -." "We claim:. method of producing an antibiotic agent which comprises cultivating under aerobic conditions an erythromycin-producing strain of treptomyces erythreus in a culture medium containing assimilable sources of carbohydrate, nitrogen and inorganic salts until substantial antibiotic activity is produced by said organism in said culture medium. [...]" - tructure first reported in without stereochemical assignments; X-ray analysis established the absolute configuration at each stereocenter in. - Quote from R.. Woodward: "Erythromycin, with all our advantages, looks at present quite hopelessly complex, particularly in view of its plethora of asymmetric centers." (In Perspectives in rganic Chemistry, Todd,., Ed., Interscience Publishers: ew York, p..) - Quote from J. Mulzer's review entitled "Erythromycin ynthesis - ever-ending tory?": "The synthesis of [...] erythromycin and [...] is probably the most extensive single project in the history of synthetic organic chemistry. This phenomenon is not rational as [they] are accessible in large quantities from fermentation [...]. It is the complexity of the molecule's structure, the plethora of stereocenters and functional groups and the magic of the medium ring that has fascinated about large research groups worldwide for more than a decade." (ngew. Chem. Int. Ed., 0, -) - Cost of erythromycin is.0 $/g, so just buy it for medchem/chembio purposes... - This molecule caught the attention of... - "Giants": Woodward, tork, Corey, Danishefsky; - "ldol Giants": Masamune, Evans, Paterson; - "European Giants": R. W. offmann, Mulzer, and recently Carreira. [...] ur modern "retrosynthetic reflex" effectuates the following disconnections: eg. erythromycin macrolactonization erythronolide seco acid of erythronolide smaller precursors Commonly used macrolactonization methods:. Corey-icolaou macrolactonization (Py-Py + PPh on the hydroxyacid, then heat; J. m. Chem. oc.,, );. Masamune thiol ester activation (Tl t u on the acyl chloride to generate a thioester, then g(ccf ) or CuTf to lactonize; J. m. Chem. oc.,, );. Mukaiyama onium salt method (-methyl--chloropyridinium iodide and on the hydroxyacid; Chem. Lett., );. Mitsunobu alcohol activation (DED + PPh on the hydroxyacid; Tetrahedron Lett.,, );. Yamaguchi mixed anhydride lactonization (,,-trichlorobenzoyl chloride + DMP on the hydroxyacid; ull. Chem. oc. Jpn,, );. Keck-teglich activation (DCC + DMP + DMP Cl on the hydroxyacid; ngew. Chem. Int. Ed.,, and J. rg. Chem., 0, );. hiina benzoic anhydride lactonization (various benzoic anhydrides + Lewis acid or base; ature Protocols, 00,, ). Examples of asymmetric control in the synthesis of stereotriads found in polyketides (for an excellent review on this topic, see: R. W. offmann, ngew. Chem. Int. Ed.,, -0):. Propionate enolate additions onto α-methylaldehydes (i.e. );. Propionate enolate additions onto α-methylesters, followed by carbonyl reduction; * * *. cetate enolate additions onto α-methylaldehydes followed by α-methylation;. Propenyl or butenyl group additions onto α-methylaldehydes, followed by hydrogenation or hydroboration;. Danishefsky's diene (methylated version) Diels-lder onto α-methylaldehydes followed by hydrolysis and ozonolysis;. Crotyl-metal and pentenyl-metal additions onto α-methylaldehydes followed by ozonolysis;. Epoxidation of an allylic alcohol bearing a methyl group at the allylic position, followed by methylcuprate addition;. ydroboration-oxidation or hydrosilylation-oxidation of the alkene motif shown on the right.

3 Y. Ishihara Erythronolide and Erythromycin aran Lab GM E. J. Corey (arvard;, ): - First total syntheses of erythronolide (JC, 00, and 0) and erythronolide (JC, 0, ), synthesized in (longest linear) steps (ca. 0.% overall, yields of the last epimerizationdeprotection steps are not reported). - students worked on it, including K. C. icolaou. - 0% yield for the macrolactonization, effectuated with a modified Corey-icolaou procedure (substituted imidazoles instead of pyridines). - Key features: Cyclic stereocontrol (i.e. not a single!); convergency amenable to the synthesis of both erythronolides and. - ard to retrosynthetically disconnect! - "Classics-worthy" synthesis! z z a z llyl-r steps steps 0 R erythronolide (R=) erythronolide (R=) ) ; r ) Cr steps r Py (resolution at this stage) T (The erythronolide synthesis simply uses a coupling rmg 0 partner with a protected hydroxyl group at C) z steps steps T erythronolide 0 K. Masamune (MIT; ): - First total synthesis of -deoxyerythronolide (JC, 0, ), synthesized in (longest linear) steps (< % overall; missing yields for the last few steps). - students worked on it. - % yield for the macrolactonization, effectuated with Masamune's own t-butylthioester method, using CuTf. - Key feature: ldol,,... a synthetic mimic of a polyketide synthase. - Textbook-style retrosynthesis! macrolactonization - Excellent demonstration of his own methodology. -deoxyerythronolide ( steps from chiral pool) C R c-x T (%, 0: dr) then -step redox LMD, then (%, : dr) TE (Coupling partner prepared from C in 0-% yield and in >00: dr) 0 TE t u a t u 0 0 TE t u c-x R ) (CCl) ) CuLi steps, then T (%, : dr) then -step [] steps including [] -deoxyerythronolide

4 Y. Ishihara Erythronolide and Erythromycin aran Lab GM R.. Woodward (arvard; posthumous, ): - First and only total synthesis of erythromycin (ll disconnections shown (JC, 0, 0, and ), synthesized in (longest linear) steps (0.00% 0 here are s) overall, of which the last 0 steps, required for the glycosidations, yielded.%). - students worked on it, including R. M. Williams. - 0% yield for the macrolactonization, effectuated with a Corey-icolaou macrolactonization. - Key features: ldols using asymmetric induction via dithiadecalins; interestingly convergent; first detailed study on the structural requirements of the erythronolide seco acid macrolactonization. - The end of the "Woodwardian era"... erythromycin 0 c t MM u + C Ms n ( steps to ( steps to make; racemic) make; racemic) steps Ra-i, with C t u, etc... 0 MM c ) a ) c ) D-proline (asym., 0%, : dr, % ee; then recrystallize) 0 steps (% overall) Py s n n n sli steps and then steps to manipulate C and C MM n n ( steps) 0 MM ( steps) erythronolide analog, and then 0 more steps to erythromycin G. tork (Columbia; ): - First total synthesis of -dihydroerythronolide (JC, 0, and ), synthesized in (longest linear) 0 steps (. % overall). 0 - nly one student:. D. Rychnovsky - % yield for the macrolactonization, effectuated with a Keck-teglich macrolactonization. - Key features: ldols performed via butenolides; convergent synthesis. macrolactonization utenolide strategy in polypropionate synthesis (JC, 0, ): -dihydroerythronolide Piv -dihydroerythronolide steps; steps; steps racemic racemic i step Pr C 0 steps steps steps steps n Mgr Piv C (R)-ethyl -hydroxy--hexynoate + steps Piv % single isomer C butenolide carbonyl attack Grignard addition steps C

5 Y. Ishihara Erythronolide and Erythromycin aran Lab GM I. Paterson (Cambridge; ): - Total synthesis of -dihydroerythronolide (TL,, and, 0, ), synthesized WE olefination in (longest linear) steps (.% overall). 0 - students worked on it. - -% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization. - Key features: Excellent use of "modern" (Evans herein) technology; convergent; macrolactonization performed on a conformationally favorable system bearing two -dihydroerythronolide olefins, precluding the use of acetonides. Ph (racemic) T 0 Ph u Tf, ipr (0%, 0g scale, : dr; both isomers needed) steps T T Ph 0 C steps to generate phosphonate; then add aldehyde fragment C-C T ) [] ) [] ) [] + Ph 0 ) a ) TTf ) C ) Znr, enolate of -pentanone 0 C Ph. J. Danishefsky (Yale; 0): - Relay synthesis of -deoxyerythronolide (JC 0,, ), synthesized in (longest linear) steps (ca. 0.0 % overall, yields of the last two steps are not reported). total synthesis from the procedures described herein would result in racemic -deoxyerythronolide. - nly one student worked on it. - % yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization. - Key feature: "Formal double " using a Lewisacid catalyzed diene aldehyde condensation (LCDC) strategy. - Great application of his own methodology. TM "diene" PG- 0 n C, ZnCl heat (%) n steps n n steps "diene"(%) then steps PG- n 0 -deoxyerythronolide n steps PG- PG- PG = TDP steps "LCDC" n n "diene" (0%) steps T ) s -M, h -dihydroerythronolide ) Zn( ) ) s TM -M, d T PG- n steps n n steps -deoxyerythronolide

6 Y. Ishihara Erythronolide and Erythromycin aran Lab GM J. Mulzer (Institut für rganische Chemie; ): crotyl - Total synthesis of erythronolide (JC, addition, 0), synthesized in (longest linear) steps carbonyl (<.% overall, yields of first few steps unclear). 0 addition - students worked on it. - >% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization. - Key features: Great use of a simple starting material from the chiral pool, glyceraldehyde; convergent; macrolactonization performed on a conformationally favorable system bearing an crotyl olefin. addition macrolactonization erythronolide -dihydroerythronolide C ) Crotylation ) Crotylation 0 ) Tosylation ) Tosylation ) cid ) cid ) ase ) ase ) CuLi ) CuLi steps steps steps n T n 0 steps Ph F steps steps uli n n (%) Ph 0 n n ) crotylboronate R. W. offmann (Universität ans-erwein-trasse; ): - Total synthesis of -dihydroerythronolide (CIEE,, 0), synthesized in a total of WE steps (.% overall). - students worked on it. - >% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization. - Key feature: Completely linear synthesis, but this synthesis is one of the shortest in total number of steps. - Excellent application of his own crotylation -dihydroerythronolide methodology. steps PG- C ) harpless E ) TPP-M PG- ) crotylboronate ) L ) PMCl ) s -M C PG- -PG PM -PG -PG c-x "crotylboronate" PG = cyclic acetal using cyclopentanone ) DDQ ) s - M-aI C PG- steps -PG c-x PG- PG- 0 -PG ) TT, Cl ) PMCl ) ; Ph P ) ent-crotylboronate C 0 PM -PG ) Yamaguchi ) Cl -dihydroerythronolide

7 Y. Ishihara Erythronolide and Erythromycin aran Lab GM D.. Evans (arvard; ): - Total synthesis of -deoxyerythronolide (TL,, ), synthesized in (longest linear) steps from β-ketoimide, add steps to make the M (.% overall). - nly one student worked on it; % yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization. - Key feature: Evans and its majesty. Convergency is also a plus. n TiCl, n(tf), n n 0 K.. Woerpel (UC Irvine; 00): - Total synthesis of -dihydroerythronolide (JC 00,, 0), synthesized in (longest linear) steps (.% overall). - nly one student worked on it. - >0% yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization. - Key feature: Great application of his own "allylsilane [+]" methodology. Convergency is also a plus. i Ph ncl, Ph CR* i c >%, >% ee R* = -pantolactone c C steps steps steps n TM PM T 0 Piv I steps n ) F (%) ) Zn( ) ) DDQ ) a, C, I ) u n, I ) Li ) TF T E. M. Carreira (ET Zürich; 00): - Total synthesis of erythronolide (CIEE 00,, 0), synthesized with the best total thus far of steps (.%). - students worked on it; % yield for the macrolactonization, effectuated with a Yamaguchi macrolactonization. - Key feature: Great application of his own "Mg-mediated nitrile oxide [+]" methodology for polyketide synthesis. T t ucl; then i T Pr, Mgr, then (%, dr >:) erythronolide steps C Ph TE steps T Ph TE T Ph steps TE repeat step 0 C steps T PM 0 n n T steps r ) Yamaguchi ) Pd() ) PCC ) Cl -deoxyerythronolide steps -dihydroerythronolide Macrolactonization: ) ince 0, all syntheses utilized the Yamaguchi macrolactonization method; ) -membered cyclic acetal over the hydroxyl groups at C and C are necessary to induce (in part) the correct conformation for the lactonization, unless there are olefins within the seco acid that rigidify the conformation; ) Woodward has contributed greatly toward examining different conformations of the macrolactonization step. symmetric stereocontrol: Development of, dithiadecalin, butenolide, "LCDC", crotylations and other methods such as [+] strategies, many of which were developed for the sake of conquering the erythronolide/erythromycin family. ther notable formal or total syntheses: Deslongchamps (CanJChem,,, ), Kinoshita (TL,, ), Kochetkov (TL,, and ), akata (CJ,, ), Chamberlin (JC,, ), Martin (JC,, ), Yonemitsu (JC 0,, ), Vogel (C 00,, ), Crimmins (L 00,, ), Martin (Tet 00,, 0), and, as a note added after this presentation, White (atchem 00 P, DI: 0.0/CEM.).