28 anionic cyclization reactions

Myers Chem 115 Anionic Cyclization Reactions Reviews: Hauser Annulation Mal, D.; Pahari, P Chem Rev 2007, 107, 1892–1918 • Annulation reactions of 3-phenylsulfonyl isobenzofuranones with Michael acceptors provide 1,4dihydroxynaphthalenes: Rathwell, K.; Brimble, M Synthesis 2007, 643–662 Mitchell, A S.; Russell, R A Tetrahedron 1995, 51, 5207–5236 • Anionic Michael-Dieckmann condensation reactions provide a powerful method for the construction of six-membered rings O O Generalized Reaction Scheme O THF, –78 ºC SO2Ph O OR LDA O O base OH O O CH3 CH3 CH3 >86% Li SO2Ph OH OH O OR X CH3 O R' X X R' Hauser, F M.; Rhee, R P J Org Chem 1978, 43, 178–180 • It is generally accepted that the transformation proceeds by an initial Michael addition reaction followed by Claisen cyclization and elimination of phenylsulfinic acid: • X = H, CN, SO2Ph, SPh, F, Br, SnR3, P(O)(OR)2, CO2CH3 • Base = LDA, LiHMDS, LiOt-Bu, KOt-Bu, NaHMDS, KHMDS, LiTMP, etc O • In a very early example, Schmid showed that esters of homophathalic acid undergo annulation reactions: O LDA O SO2Ph CO2CH3 CH3 CH3 O OLi O CH3 CH3 SO2Ph SO2Ph NaOMe, MeOH OCH3 OCH3 + O OH O O CO2CH3 CH3 OLi 95 ºC, 50% CH3 CO2CH3 O Ph S O O OH O (relative stereochemistry not determined) CH3 CH3 OH OLi O O CH3 CH3 LiO SO2Ph O CH3 CH3 SO2Ph Eisenmuth, W.; Renfroe, H B.; Schmid, H Helv Chim Acta 1965, 48, 375–379 Fan Liu Myers Chem 115 Anionic Cyclization Reactions Kraus Annulation • Conjugate addition of a phenyl sulfoxide derivative followed by intramolecular condensation and thermal elimination of phenylsulfenic acid gives 1-hydroxynaphthalenes: CO2Et CO2Et LDA O S Ph O O S O CH3 CH3 O OCH3 O O LDA, HMPA O THF, –78 ºC CH3 SOPh Ph O O O CH3 Li THF, –78 ºC O • 3-cyanoisobenzofuranones are effective substrates for anionic cyclizations: Li CN CN O –78 ! ºC K2CO3, MeI acetone, 60 ºC OCH3 >50% 66 ºC Kraus, G A.; Sugimoto, H Tetrahedron Lett 1978, 26, 2263–2266 OH O Comparison of Hauser and Kraus Annulations CH3 CH3 70% • While yields for the two methods can be similar in some cases, in other cases the Kraus annulation was found to be more effective, likely because the cyanoisobenzofuranone nucleophile is less hindered and more soluble in the reaction medium: O O Hauser, F M.; Rhee, R P J Org Chem 1978, 43, 178–180 OH O O O • A closely related method was reported by van Leusen, which involves thermal elimination of phenylsulfinic acid: O CH3O SO2Ph THF, –78 ºC O CH3O Li SO2Ph CH3 –78 ! 65 ºC + CH3O OH 35% CH3 O OH CO2Et O S Ph O O LiOt-Bu CO2Et NaH, DME, 23 ºC CO2Et CO2Et MeOH, 40 ºC CO2Et O OH O CH3O Wildeman, J.; Borgen, P C.; Pluim, H.; Rouwette, P H F M.; van Leusen, A M Tetrahedron Lett 1978, 25, 2213–2216 O O 76% O CH3O2C O LiOt-Bu CN THF, –60 ºC CH3 O CH3O Li CN –60 ! 23 ºC CH3O O 86% O CH3 Hauser, F M.; Combs, D W J Org Chem 1980, 45, 4071–4073 Mal, D.; Patra, A.; Roy, H Tetrahedron Lett 2004, 45, 7895–7898 Fan Liu Myers Chem 115 Anionic Cyclization Reactions • In the following example, the Kraus annulation was reported to be a "much cleaner reaction": • Staunton-Weinreb Annulations • Staunton and Weinreb showed independently in 1979 that o-toluates are suitable nucleophiles for anionic cyclization reactions CH3O CH3O O CH3O O OH O cyclohexenone LDA, HMPA O O THF, –78 ºC –78 ! 23 ºC Li SO2Ph SO2Ph CH3O "moderate yield" OCH3 OH CH3O CH3O CH3O O CH3O O CH3O O LDA OCH3 CH3O THF, –78 ºC CH3 O Li OH O cyclohexenone LDA, HMPA CH3O O O THF, –78 ºC Li CN CN OH O –78 ! 23 ºC TBSO OH "a much cleaner reaction" 80% CH3O H CH3 O O TBSO O CH3O CH3 O H O Li, T.-T.; Walsgrove, T C Tetrahedron Lett 1981, 22, 3741–3744 40% Dodd, J H.; Weinreb, S M Tetrahedron Lett 1979, 38, 3593–3596 • Sammes Annulation O • It was shown that a phthalide anion is a suitable reaction partner en route to 1-hydroxynaphthalenes: CH3O CH3O O O O O CH3O CH3 O THF, –40 ºC CH3O CH3O O LDA OCH3 OCH3 LDA, HMPA O THF, –78 ºC OCH3 CH3 O OCH3 CH3O CH3 Li –40 ! 23 ºC Li 58% CH3O OH O O OCH3 CH3 CH3O OCH3 BF3•OEt2 CH3 CH2Cl2, 23 ºC 43% O CH3O OH CH3O OH O CO2CH3 O OCH3 CH3O CH3 LDA, THF –15 ºC, 70% CH3O CH3 O O Broom, N J P.; Sammes, P G J Chem Soc Chem Commun 1978, 162–164 Broom, N J P.; Sammes, P G J Chem Soc Perkin Trans 1981, 465–470 OCH3 Evans, G.; Leeper, F J.; Murphy, J A.; Staunton, J J Chem Soc Chem Commun 1979, 205– 206 Leeper, F J.; Staunton, J J Chem Soc Chem Commun 1979, 5, 206–207 Fan Liu Myers Other Nucleophiles • This annulation reaction can also be done in a single step: • Phenylsulfenylphthalide, originally reported by Kraus, was also found to be a competent annulation partner: O CH3O CH3O O OCH3 CH3O Chem 115 Anionic Cyclization Reactions CH3 O LDA CH3 OCH3 THF, –78 ºC O CH3 O O –78 ! 23 ºC CH3O O Li O CH3O CH3O OH O OH O OEt LDA, HMPA OEt O THF, –78 ºC SPh –78 ! 23 ºC CH3O Li SPh CH3O OH 53% O CH3 CH3O CH3 Kraus, G A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.; Prugh, S J Org Chem 1983, 48, 3439– 3944 79% • A phenyl ester was employed in a synthetic approach to (+)-pillaromycinone: O H H OTBS CH3 CH3O CO2Ph CH3 CH3O CH3O LDA H CO2Ph THF, –78 ºC • In the following example, use of the traditional Hauser cyclization substrate, 3-phenylsulfonyl isobenzofuranone, did not afford the desired product Using phenylsulfenyl phthalide, however, provided the desired product in good yield: O O O Li CH3O CH3O O O LiOt-Bu O OCH3 OCH3 O CH3O CH3 THF, –78 ºC CH3O OH O H H OTBS CH3 H O SPh Li SPh CeCl3 –78 ! 26 ºC 62% CH3O OH O O HO CH3O White, J D.; Nolen, E G.; Miller, C H J Org Chem 1986, 51, 1152–1155 • In the Stauton-Weinreb annulation reaction, it is imperative that an alkoxy group is present ortho to the ester group to prevent self-coupling of the nucleophile OCH3 OCH3 CH3 Hauser, F M.; Dorsch, W A.; Mal, D Org Lett 2002, 4, 2237–2239 Fan Liu Myers Chem 115 Anionic Cyclization Reactions • Homophthalide anhydrides were also found to be good cyclization partners: • Alternatively, homophthalide anhydrides can be used: O CO2CH3 Ph OH O O NaH O O THF, ºC CO2CH3 CO2CH3 O O O NaH O CO2CH3 –78 ! 23 ºC Ph Ph O O O THF, ºC 94% OH O Ph O –78 ! 23 ºC O HO2C Na Na O 83% (relative stereochemistry not determined) Tamura, Y.; Sasho, M.; Nakagawa, K.; Tsugoshi, T.; Kita, Y J Org Chem 1984, 49, 473–478 Tamura, Y.; Sasho, M.; Nakagawa, K.; Tsugoshi, T.; Kita, Y J Org Chem 1984, 49, 473–478 • Synthesis of Cyclohexanone Derivatives (Non-Aromatizing Cyclizations) • Michael-Dieckmann cyclization of o-toluate anions with Michael acceptors affords cyclohexanone derivatives: Swenton Annulation • Swenton showed that Schmid's anionic cyclization nucleophile (shown on page 1) can be applied to quinone monoacetals under modified conditions: OH CH3O CH3O O O O OH CH3 CO2CH3 LDA OCH3 CO2CH3 O THF, –78 ºC CH3 OCH3 CH3 ºC Li NaH, THF + CO2CH3 CH3O OCH3 25 ºC, 60% CH3O2C CH3O OCH3 CH3O O O O OCH3 O CO2CH3 O CH3 OH NaH, THF + CO2CH3 CH3 CH3O OCH3 HCl, CH3OH 65 ºC, 40% CH3 Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y Synthesis 1986, 785–786 25 ºC CH3O2C CH3 OCH3 OCH3 pTSA, C6H6 80 ºC, 40% CH3O N EtO CH3O OCH3 CH3 O O O LDA THF, –78 ºC O OCH3 N EtO O Li O OH CH3O , EtOH CH3 CH3O2C OCH3 Chenard, B L.; Anderson, D K.; Swenton, J S J Chem Soc Chem Commun 1980, 932–933 –78 ! 24 ºC Boger, D L.; Zhang, M J Org Chem 1992, 57, 3974–3977 Clive, D L J.; Sedgeworth, J J Heterocyclic Chem 1987, 24, 509–511 OH O N EtO O 83% Fan Liu Myers Chem 115 Anionic Cyclization Reactions • Stereoselective Synthesis of Cyclohexanone Derivatives • One of the first stereoselective anionic cyclization reactions was reported in 1986 in the synthesis of olivin trimethyl ether: • Synthesis of bioxanthracene (–)-ES-242-4: O CH3O O CH3O CH3O O DME, –78 ºC O CH3O CH3O LDA O CH3 Li CO2CH3 –78 ! 23 ºC dehydration O CH3O CH3 OMOM CH3O CO2CH3 LDA CO2CH3 THF, –78 ºC CH3 CH3O Li –78 ! ºC 55% (conditions not specified) CH3O CH3O CH3O Li OCH3 O OCH3 LDA, DMPU CH3O OCH3 THF, –78 ºC CH3O O CH3O OH CH3O O OCH3 O CH3O CH3 OH OH H3C CH3O H O O OH O CH3 CH3O CH3 CH3 OMOM single diastereomer H steps CH3 O O CH3O CH3 H3C CH3O O H H O CH3O O >51% CH3O CH3 OH (–)-ES-242-4 O CH3 Tatsuta, K.; Yamazaki, T.; Mase, T.; Yoshimoto, T Tetrahedron Lett 1998, 39, 1771–1772 OH O OCH3 Franck, R W.; Bhat, V.; Subramaniam, C S J Am Chem Soc 1986, 108, 2455–2457 Fan Liu Myers Chem 115 Anionic Cyclization Reactions • Stereoselective anionic cyclizations were employed in the synthesis of tetracycline antibiotics An initial experiment using an organostannane showed that Michael addition occurred with complete stereoselectivity: • By using a phenyl ester and LDA for anion formation, Michael-Claisen cyclization occurred in high yields and with excellent diastereoselectivities: CH3 H Et N(CH3)2 O N CH3 Sn(CH3)3 OCH3 CH3O BocO CH3 O O Li OCH3 n-BuLi THF, –78 ºC CH3O O THF, –78 ºC O BocO –78 ! ºC BnO2CO O H N(CH3)2 O OBn O OTBS Li OPh LDA, TMEDA OPh N O TBSOTf, 98% OBn O OTBS O OH N(CH3)2 H3C H H H OH H3C H H NH2 N(CH3)2 HO O O OH O H O O TBSO O CH3O H3CO OTBS • The stereochemical outcome in the addition step is consistent with a pseudoaxial addition to the enone, from the "-face opposite the bulky tert-butyldimethylsilyloxy substituent: H2, Pd, THF BocO (–)-Doxycycline OBn single diastereomer HF, MeCN MeOH, 90% N O OBn H3C H H O H N(CH3)2 O N N(CH3)2 CH3 O OTBS OBn 79%, dr > 20:1 N(CH3)2 Li OPh LDA, TMEDA OPh BocO OH O THF, –78 ºC O BocO –78 ! –10 ºC H O N(CH3)2 O N O Nuc H OBn N(CH3)2 O N O O OTBS O OTBS (CH3)2N OBn H H N(CH3)2 OH NH2 HO O OH O H O Minocycline Sun, C.; Wang, Q.; Brubaker, J D.; Wright, P.; Lerner, C D.; Noson, K.; Charest, M.; Siegel, D R.; Wang, Y.-M.; Myers, A G J Am Chem Soc 2008, 130, 17913–1717927 Carpenter, T A.; Evans, G E.; Leeper, F J.; Staunton, J.; Wilkinson, M R J Chem Soc Perkin Trans 1984, 1043–1051 O H2, Pd black (CH3)2N H H N(CH3)2 CH3OH, dioxane O N HF, CH3CN, 74% BocO OH O O OTBS OBn 83%, dr > 20:1 Charest, M G.; Lerner, C D.; Brubaker, J D.; Siegel, D.; Myers, A G Science 2005, 308, 395–398 Sun, C.; Wang, Q.; Brubaker, J D.; Wright, P.; Lerner, C D.; Noson, K.; Charest, M.; Siegel, D R.; Wang, Y.-M.; Myers, A G J Am Chem Soc 2008, 130, 17913–1717927 Fan Liu Myers Chem 115 Anionic Cyclization Reactions • In the most recently reported route, two consecutive stereoselective anionic cyclization reactions were used to construct tetracycline antibiotics In the first cyclization, addition of KHMDS to deprotonate the final Claisen product was crucial to prevent quenching of the enolate intermediate by proton transfer from the product or methanol: CH3O CO2CH3 CH3O LDA CO2CH3 THF, –78 ºC Li CH3 N(CH3)2 H3C CH3 OBn O O Na CH3O N O –78 ! 23 ºC N(CH3)2 NaHMDS, THF O CH3O LiBr N O O CH3O O OH H O –78 ! –15 °C 80%, dr > 20:1 Li N(CH3)2 OBn H H O O OTBS O O CH3 CH3 O H O O CH3 CH3 N(CH3)2 99%, single diastereomer O O N N –78 ! –15 °C O H CH3 H H H H3C CH3 KHMDS CO2Ph O H CH3 OBn H R H H OBn H O OH OBn White, J D.; Demnitz, F W J.; Xu, Q.; Martin, W H C Org Lett 2008, 10, 2833–2836 • In the examples above, an alkoxy substituent must be present ortho to the ester functionality to prevent dimerization of the nucleophile H H N(CH3)2 O N R OBn OH O O OTBS OBn steps tetracycline antibiotic candidates • More than 3000 fully synthetic novel tetracycline antibiotic candidates have been prepared using stereoselective anionic cyclization reactions • This limitation was overcome in tetracycline synthesis by deprotonating the substrate in the presence of the Michael acceptor: N CH3 H N(CH3)2 + N OPh O O O O OTBS OBn LDA, HMPA N H H N(CH3)2 O N –95 ! –50 ºC OH O O OTBS OBn 76%, dr > 20:1 Kummer, D A.; Li, D.; Dion, A.; Myers, A G Chem Sci 2011, 2, 1710–1718 Charest, M G.; Lerner, C D.; Brubaker, J D.; Siegel, D.; Myers, A G Science 2005, 308, 395–398 Sun, C.; Wang, Q.; Brubaker, J D.; Wright, P.; Lerner, C D.; Noson, K.; Charest, M.; Siegel, D R.; Wang, Y.-M.; Myers, A G J Am Chem Soc 2008, 130, 17913–1717927 Charest, M G.; Lerner, C D.; Brubaker, J D.; Siegel, D.; Myers, A G Science 2005, 308, 395–398 Fan Liu Myers Chem 115 Anionic Cyclization Reactions • Another strategy permitting cyclization of aromatic ester substrates lacking ortho substituents involved in situ anion formation by lithium-halogen exchange, in the presence of the Michael acceptor: • A stereoselective anionic cyclization reaction is used in the industrial synthesis of a novel tetracycline antibiotic candidate: LDA (1.13 equiv) Et3N•HCl (0.5 mol%) F CH3 H Br OPh N(CH3)2 O + O N O O OTBS OBn H H N(CH3)2 Bn2N O n-BuLi, THF OPh OH O Li OPh Bn2N OBn O (600 g) OBn O OTBS LiHMDS (0.11 equiv) OBn O N –100 ! –70 ºC 81%, dr > 20:1 THF, –70 ºC F LiHMDS (0.92 equiv) H N(CH3)2 O N –78 ! –10 ºC O H N(CH3)2 Br + OPh CH3O O O N O O OTBS OBn H H N(CH3)2 n-BuLi, THF –100 ! ºC 75%, dr > 20:1 O N CH3O OH O OBn O OTBS (524 g) O OTBS F H O OBn N N H Charest, M G.; Lerner, C D.; Brubaker, J D.; Siegel, D.; Myers, A G Science 2005, 308, 395–398 Sun, C.; Wang, Q.; Brubaker, J D.; Wright, P.; Lerner, C D.; Noson, K.; Charest, M.; Siegel, D R.; Wang, Y.-M.; Myers, A G J Am Chem Soc 2008, 130, 17913–1717927 N(CH3)2 OH NH2 O OH OH O H O Eravacycline • In the example above, attempted cyclization by direct deprotonation of the corresponding omethylnaphthalene was not successful H O F H H N(CH3)2 steps O N Bn2N OBn OH O O OTBS OBn 94% (934 g) • The use of a small amount of Et3N•HCl in the deprotonation step, which provides a source of LiCl, was found to be crucial in providing consistent and clean cyclization results on a manufacturing scale • Because the presence of excess LDA appeared to promote the formation of byproducts, a weaker base, LiHMDS, was used as a substitute to deprotonate the acidic proton in the final product and drive the Claisen reaction to completion Ronn, M.; Zhu, Z.; Hogan, P C.; Zhang, W.-Y.; Niu, J.; Katz, C E.; Dunwoody, N.; Gilicky, O.; Deng, Y.; Hunt, D K.; He, M.; Chen, C.-L.; Sun, C.; Clark, R B.; Xiao, X.-Y Org Process Res Dev 2013, 17, 838–845 Fan Liu Myers Chem 115 Anionic Cyclization Reactions • Synthesis of a dideoxydynemicin analog: Examples in Synthesis • Synthesis of 1,4-Dihydroxynaphthalene Derivatives OH H N OH t-BuLi O LDA O THF, –78 ºC SO2Ph THF, –78 ºC Li SO2Ph CH3O O CH3O O CH3 O O OH –78 ! 23ºC O OCH3 OCH3 OH • Kraus annulation proved to be ineffective for the synthesis of dynemicin A itself Instead, a DielsAlder cycloaddition was employed: OEt H N O KHMDS, THF, –78 ºC TMSCl•Et3N, –20 ºC TMSO CH3 CO2Si(i-Pr)3 O OCH3 TMSO TMSO m-CPBA, CH2Cl2 ºC, 65% O H O O TMSO –20 ! 55ºC, 75% OTMS O CH3O CO2CH3 Methylation (conditions not specified) CH3O O LDA O O O THF, –78 ºC CH3O Li SO2Ph CH3O SO2Ph OH O H HN CH3 CO2H H O OH O TMSO O OCH3 CH O CH3O OH H HN O K2CO3, Me2SO4, acetone, 65% PhSH, pTSA C6H6, 80 ºC, 93% Li CN CN OEt O O O OCH3 OCH3 O O O O O O • Two consecutive anionic annulation reactions were employed for the synthesis of the core structure of anthracyclines: CH3 OH Dynemicin A MnO2, 3HF•Et3N H H HN CH3 CO2Si(i-Pr)3 O O THF, 23 ºC, 53% TMSO OCH3 H OR OH R = TMS CO2CH3 CH3O OCH3 87% Hauser, F M.; Prasanna, S J Org Chem 1979, 44, 2596–2598 Myers, A G.; Fraley, M E.; Tom, N J J Am Chem Soc 1994, 116, 11556–11557 Myers, A G.; Fraley, M E.; Tom, N J.; Cohen, S B.; Madar, D J Chem Biol 1995, 2, 33–43 Myers, A G.; Tom, N J.; Fraley, M E.; Cohen, S B.; Madar, D J J Am Chem Soc 1997, 119, 6072–6094 Fan Liu 10 Myers Chem 115 Anionic Cyclization Reactions O • Synthesis of Trioxacarcin A: CH3O CN O CH3 MOMO O CH3 LiOt-Bu Li CN THF, –78 ºC MOMO O H O CH3O CH3O Li THF, –78 ºC OCH3 CN OBn OTBS –78 ! ºC CN 94% OTBS O O CH3 O LiHMDS O OPMB CH3O CH3 CH3O O Si(CH3)3 CH nPr O CH3 O O –78 ! –22 ºC Me2SO4 CH3O OH O –22 ! 23 ºC CH3O CH3O Si(CH3)3 CH nPr O CH3 O O H OH OBn OTBS Liau, B B.; Milgram, B C.; Shair, M D J Am Chem Soc 2012, 134, 16765–16772 H3C HO CH3O CH3O O CH3 O H OH O CH3 CH3 O HO CH3 O H O OH O H H O H OAc CH3 CH3O O H H O • Synthesis of viridicatumtoxin B: CH3 CH3O CH3 OBn O OH CH3O NaH + O OH O CH3O OCH3 CH3O OCH3 O OTBS MOMO O OPMB O ! 23 ºC DBU toluene, 65 ºC OBn O OH CSA, CH2Cl2 25 ºC, 99% trioxacarcin A CH3 CH3 OCH3 OCH3 CH3 CH3O Svenda, J.; Hill, N.; Myers, A G Proc Natl Acad Sci 2011, 108, 6709–6714 Magauer, T.; Smaltz, D J.; Myers, A G Nat Chem 2013, 5, 886–893 OCH3 steps CH3O OBn O OBn OH O OH (±) O O Si(CH3)3 O N PhO O OBn t-BuOK toluene, 25 ºC, 91% TBAF, NH4F THF, 25 ºC, 86% CH3 CH3O CH3 CH3 OCH3 OCH3 H OBn OH OH O O N OBn dr = : Nicolaou, K C.; Nielewski, C.; Hale, C R H.; Ioannidou, H A.; ElMarrouni, A.; Koch, L G Angew Chem Int Ed 2013, 52, 8736–8741 Fan Liu 11 Myers • Synthesis of 1-Hydroxynaphthalene Derivatives • In Danishefsky's synthesis of dynemicin, a homophthalide anhydride substrate was found to be a superior cyclization partner, whereas the Kraus annulation failed to provide the desired product • Synthesis of tetracycline: Li CH CH3 LDA O O CH3O Chem 115 Anionic Cyclization Reactions OH • In this synthesis, a series of oxidation reactions provided the anthraquinone of dynemicin A: O THF, –40 ºC H O CH3O NHCbz OBn H N OBn O CH3 OH OCH3 HO CH3 H OH O OBn OH CH3O HO CH3 15 steps H OH O MOMO O NHCbz OBn OBn CH3O O MOMO O O O O O THF, ºC MOMO O OH N(CH3)2 OH O OH O H O H Li LiHMDS PhI(OCOCF3)2 THF, ºC NH2 HO CO2MOM O 80% MOMO SOCl2, Et3N CH2Cl2 –30 ºC, 90% NHCbz H OBn CH3 H HN MOMO CH3 CO2MOM O OCH3 (–)-Tetracycline H Tatsuta, K.; Yoshimoto, T.; Gunji, H.; Okado, Y.; Takahashi, M Chem Lett 2000, 646–647 MOMO O OH • Synthesis of a benanomicinone analogue: CH3O OCH3 CO2CH3 SOPh CH3O Br CH3O LiOt-Bu THF, DMSO OCH3 CO2CH3 SOPh CH3O Br OCH3 MOMO OCH3 Li H N CH3 CO2MOM OCH3 H O CH3O OCH3 OCH3 O OCH3 OCH3 CH3O 31% (2 steps) OH O 15% (4 steps) CH3 CO2H O air, THF, 25 ºC MgBr2, Et2O ! 25 ºC OCH3 H OH O OH Dynemicin A OCH3 CH3O Br OCH3 OCH3 MOMO OH O O H HN CH3 CO2CH3 Hauser, F M.; Liao, H.; Sun, Y Org Lett 2002, 4, 2241–2243 CH3O CH3 CO2CH3 (CH3)2SO4, K2CO3 acetone Shair, M D.; Yoon, T.-Y.; Danishefsky, S J Angew Chem Int Ed 1995, 34, 1721–1723 Shair, M D.; Yoon, T.-Y.; Mosny, K K.; Chou, T C.; Danishefsky, S J J Am Chem Soc 1996, 118, 9509–9525 Fan Liu 12 Myers • The Shair group found that a particularly difficult annulation reaction was best carried out using a benzyl fluoride as the nucleophile: CH3O CH3 Chem 115 Anionic Cyclization Reactions CH3 n Si(CH3)3 Pr O O O O BnO H TBSO O OCH3 CH3O O CH3O + F H F OCH3 O OCH3 OCH3 OTBS OBn + O O O OCH3 • A bidirectional approach to hibarimicinone: note the use of two different nucleophiles to form the C and F rings: O On CH3 Pr Si(CH3)3 CH3 CH3 CH3 n Si(CH3)3 Pr O O O O O CH3O CH3O OBn O BnO H TBSO NC LiTMP, THF, –78 ºC HMDS, –78 ! –35 ºC MgBr2•OEt2 BnO OCH3 SPh H OCH3 OTBS OBn O O O CH3 Pr Si(CH3)3 CH3 On O OBn racemic–atropisomers –35 ! ºC LiHMDS, THF, –78 ! °C; KHMDS, ! 23 ºC 50–59% CH3 NaHCO3, TFE H2O, 80 ºC 59% (2 steps) CH3 F H H H F O HO OCH3 OCH3 OTBS OBn O O BnO H TBSO O CH3 O Pr Si(CH3)3CH3 On CH3 OCH3 CH3O CH O Si(CH ) 3 CH3 nPr O OH OBn O O O BnO H TBSO CH3O CH3O Si(CH3)3 CH3 nPr O OH O O O O BnO H TBSO CH3O CH3O CH O Si(CH ) 3 CH3 nPr O OH O O O OCH3 H OH O OCH3 OCH3 OCH3 OTBS OBn O BnO HO OCH3 OH OBn H O CH3 Pr Si(CH3)3CH3 On O ~1.3:1 mixture of separable atropisomers OTBS OBn O O SPh H DMTSF, DTBMP, MeCN ! 23 ºC CH3 Pr CH Si(CH3)3 On O atropisomers OCH3 • The electronegative fluorine atom stabilizes the anion and is sterically unencumbered CH3 • In the absence of the fluorine atom, Michael addition occurred at –78 ºC but the subsequent Claisen cyclization could never be driven to completion The alternative Hauser and van Leusen substrates did not afford the desired product • Addition of HMDS prior to warming quenches excess LiTMP, which prevents substrate decomposition in the subsequent Claisen condensation step Liau, B B.; Milgram, B C.; Shair, M D J Am Chem Soc 2012, 134, 16765–16772 CH3O Si(CH3)3 CH3 nPr O OH OBn O O O BnO H TBSO C H OTBS OBn F BnO HO OCH3 O O CH3 Pr Si(CH3)3CH3 On O OH OBn atropisomer (75%) atropisomer (89%) Liau, B B.; Milgram, B C.; Shair, M D J Am Chem Soc 2012, 134, 16765–16772 Fan Liu 13 Myers Chem 115 Anionic Cyclization Reactions Synthesis of Annulation Substrates PhS CH3 • Hauser Annulation Substrates EtO2C SR H O CO2H O PhSH, C6H6 THF, –78 ºC PhSSPh (4.4 equiv) CO2Et CO2Et OCH3 LDA (3 equiv) SPh THF, –78 ºC PhSSPh (2.2 equiv) –78 ! 23 °C SPh SO2Ph TFA, H2O CO2Et OCH3 OCH3 O m-CPBA, K2CO3 OCH3 OCH3 CH2Cl2, 100% CH3O CH3O OCH3 OCH3 O SPh O O PhO2S O 95% SPh O O CH3O CH3O SPh 100% CO2Et O Hauser, F M.; Rhee, R P J Org Chem 1978, 43, 178–180 TFA, H2O OCH3 OCH3 PhS O CH3 CH3O CH3O 55% CH3 OCH3 O yield not provided LDA (6 equiv) OCH3 OCH3 O m-CPBA, CH2Cl2 OCH3 EtO2C CH3O CH3O SO2Ph O SPh O PhS Hauser, F M.; Gauuan, P J F Org Lett 1999, 1, 671–672 83% O MOMO Hauser, F M.; Rhee, R P.; Prasanna, S Synthesis 1980, 72–74 CH3 MOMO H NEt2 O PhSO2Na, AcOH 80 ºC, 66% MOMO SO2Ph O MOMCl, DIPEA, DMF –40 ! 23 °C, 74% CH3 MOMO O Tatsuka, K.; Inukai, T.; Itoh, S.; Kawarasaki, M.; Nakano, Y J Antibiot 2002, 55, 1076–1080 SPh O LDA, HMPA • In the following example, the sulfoxide intermediate underwent Pummerer rearrangement and the resulting sulfonium ion was trapped by the carboxylic acid: O PhSSPh OCH3 O –78 ! °C, 49% OCH3 O O CH3 O Kraus, G A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.; Prugh, S J Org Chem 1983, 48, 3439–3444 CO2Et NBS, CCl4 h", 84% PhSH, KOH EtOH, 97% O SPh O SPh m-CPBA, CH2Cl2 O CO2H Ac2O 60% (3 steps) O O O KOH, MeOH, H2O Hauser, F M.; Dorsch, W A Org Lett 2003, 5, 3753–3754 Fan Liu 14 Myers Chem 115 Anionic Cyclization Reactions O CH3 CO2Et S Ph CN NBS CHO NaSPh, EtOH CO2Et OH NaIO4 KCN, HCl O yield not provided Hauser, F M.; Rhee, R P J Org Chem 1978, 43, 178–180 OH OH H2O, ºC, 77% CN (COCl)2, C5H5N O O DMF, MeCN –15 ºC, 82% O Freskos, J N.; Morrow, G W.; Swenton, J S J Org Chem 1985, 50, 805–810 Kraus, G A.; Sugimoto, H Tetrahedron Lett 1978, 26, 2263–2266 SPh CH3 CN LDA (1 equiv) CHO CO2Et OCH3 THF, –78 ºC PhSSPh (1.1 equiv) CO2Et OCH3 KCN, NaHSO3 OH OCH3 OCH3 87% O CN SiO2, 50% O 50% (2 steps) O O Hauser, F M.; Rhee, R P.; Prasanna, S Synthesis 1980, 72–74 CH3 CN CN LDA, –78 ºC O O O CN CN • Kraus Annulation Substrates O CO2Et OCH3 ClSO2NCO, 30% NBS, (PhCO2)2 CCl4, 80 ºC NaCN, EtOH CO2Et OCH3 CCl4, 80 ºC O OCH3 O 155 ºC, 49% 80 ºC, 55% O CO2 NBS, (PhCO2)2 O Kraus, G A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.; Prugh, S J Org Chem 1983, 48, 3439–3444 Kraus, G A.; Sugimoto, H Tetrahedron Lett 1978, 26, 2263–2266 O CHO CONEt2 OCH3 CH3 CN NaCN, PTSA O THF, H2O ! 23 °C, 95% Li, T.-T.; Wu, Y L J Am Chem Soc 1981, 103, 7007–7009 OCH3 O H NEt2 CH3 MOMO CN O CH3 TMSCN, CH2Cl2 KCN (cat), 18-crown-6 ! 23 °C O CH3 MOMO O AcOH, 23 ºC, 77% Svenda, J.; Hill, N ; Myers, A G Proc Natl Acad Sci 2011, 108, 6709–6714 Magauer, T.; Smaltz, D J.; Myers, A G Nat Chem 2013, 5, 886–893 Fan Liu 15 ... 83% Fan Liu Myers Chem 115 Anionic Cyclization Reactions • Stereoselective Synthesis of Cyclohexanone Derivatives • One of the first stereoselective anionic cyclization reactions was reported in... 17913–1717927 Fan Liu Myers Chem 115 Anionic Cyclization Reactions • In the most recently reported route, two consecutive stereoselective anionic cyclization reactions were used to construct tetracycline... Subramaniam, C S J Am Chem Soc 1986, 108, 2455–2457 Fan Liu Myers Chem 115 Anionic Cyclization Reactions • Stereoselective anionic cyclizations were employed in the synthesis of tetracycline antibiotics