33 methods for ring contraction

Myers Chem 115 Methods for Ring Contraction • Chiral-pool starting materials have been much used as substrates for the Favorskii reaction, affording functionalized, optically active cyclopentanes Recent Reviews: Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q Chem Rev 2011, 111, 7523–7556 O Silva, Jr L F Tetrahedron 2002, 58, 9137–9161 O H2O2 CH3 • Ring contraction reactions can be grouped into three general categories based on mechanism: O O X NaOH Nu: O O Nu CO3CH3 CH3 Carbenoid O R CH3 THPO Lee, E.; Yoon, C H J Chem Soc., Chem Commun 1994, 479–481 • For example, the ring contraction of a (+)-pulegone derivative has been used in the synthesis of several terpenoid natural products CH3 CH3 CH3 Br2 Anionic Ring Contractions Favorskii Rearrangement O • The Favorskii reaction leads to the rearrangement of an !-halo cycloalkanone upon treatment with base This reaction proceeds through a cyclopropanone intermediate that is opened by nucleophilic attack O O Cl 80% R Cationic O H CH3 CH3 THPO O CH3 NaOCH3 CH3OH Nu: M THPO 81% (2 steps) CH3 (–)-Carvone Anionic O DHP, p-TsOH 90% CH3 Nu O Cl CH3 TMSCl CH3 O CH3 Br Br O CO2CH3 CH3OH CH3 CH3 CH3 CH3 60–67% (2 steps) (+)-Pulegone OCH3 OCH3 NaOCH3 CH3 Et2O NaOCH3 Et2O, 35 °C, h 56–61% Organic syntheses; Wiley & Sons: New York, 1963; Coll Vol No 4, pp 594 AgNO3 Br H2O, t-BuOH OH H Cope, A C.; Graham, E S J Am Chem Soc 1951, 73, 4702–4706 Loftfield, R B J Am Chem Soc 1951, 73, 4707–4714 H O H 71% CH3 CH3 H H CH3 CH3 (+)-Epoxydictymene CO2H OH O H Ag+ CH3 CH3 • In some cases, enolization is not possible, precluding cyclopropanone formation An alternate mechanism involves formation of a tetrahedral intermediate that promotes alkyl migration Br CH3 O H H O CH3 CH3 CH3 (–)-Iridomyrmecin (+)-Acoradiene Common intermediate: Furniss, B S.; Hannaford, A J.; Smith, P W G.; Tatchell, A R Vogel's Textbook of Practical Organic Chemistry 5th ed Longman: London, 1989 (+)-Epoxydictymene: Jamison, T F.; Shambayati, S.; Crowe, W E.; Schreiber, S L J Am Chem Soc 1997, 119, 4353–4363 (–)-Iridomyrmecin: Wolinsky, J.; Gibson, T.; Chan, D.; Wolf, H Tetrahedron 1965, 21, 1247–1261 (+)-Acoradiene: Kurosawa, S.; Bando, M.; Mori, K Eur J Org Chem 2001, 4395–4399 Matt Mitcheltree Myers Chem 115 Methods for Ring Contraction Quasi-Favorskii Rearrangement • Also referred to as the negative-ion pinacol rearrangement, the quasi-Favorskii rearrangement involves an alkyl shift with concomitant nucleophilic displacement of an aligned leaving group • A common application of the quasi-Favorskii rearrangement is in the rearrangement of fused polycycles OH HO • These fragmentations are generally accelerated by oxyanion formation OMs MsCl (1 equiv), pyr CH3 KOt-Bu HO CH3 OTs KOt-Bu CH3 THF O CH3 H CH3 CH3 O 60% (2 steps) CH3 + OTs O O O 90%, 89 : 11 Hamon, D P G.; Tuck, K L Chem Commun 1997, 941–942 OH Br LAH O H CH3 CH3 H CHO Br O H CH3 HO H (±)-Hinesol Marshall, J A.; Brady, S F J Org Chem 1970, 35, 4068–4077 H CH3 98% Harmata, M.; Bohnert, G.; Kürti, L.; Barnes, C L Tetrahedron Lett 2002, 43, 2347–2349 CH3 OH LiOH • A quasi-Favorskii ring contraction was employed by Harding in the synthesis of (±)-sirenin The stereochemical outcome of this rearrangement suggests formation of a tetrahedral intermediate that undergoes alkyl shift with halide displacement, rather than cyclopropanone formation as in the classic Favorskii rearrangement O H AgNO3 Cl CH3 H CH3OH OBn CH3O Cl Ag+ OH O O HO t-BuOH, 65 °C OTs CH3 OH CH3 O O O H O O O O OTs H 87% H CH3 CH3 H CH3O2C OBn H OBn 53% CH3 O O O H CH3 O (±)-Confertin H CH3 CH3 H OBn Heathcock, C H.; DelMar, E G.; Graham, S L J Am Chem Soc 1982, 104, 1907–1917 CH3 HO H OH (±)-Sirenin Harding, K E.; Strickland, J B.; Pommerville, J J Org Chem 1988, 53, 4877–4883 Matt Mitcheltree Myers Chem 115 Methods for Ring Contraction Quasi-Favorskii Rearrangement Carbenoid Ring Contractions • Harmata has showcased the power of the quasi-Favorskii rearrangement in the synthesis of several terpenoid natural products Wolff Rearrangement Reviews: Kirmse, W Eur J Org Chem 2002, 2193–2256 LAH KH Meier, H.; Zeller, K.-P Angew Chem Int Ed 1975, 14, 32–43 H Cl O CHO Cl O • The Wolff rearrangement involves the transformation of an !-diazo ketone via carbene or carbenoid to a ketene, which undergoes further transformation to form a stable adduct 76% (2 steps) Stereochemistry established by X-ray • The Wolff rearrangement may be induced by heat, Ag(I) salts, or light O R2 R1 h", #, or AgI H H R1 H CH3 CH3 O Nu R2 R1 R2 Nu = -OCH3, -OBn, -OH, -NR2, SR, etc OH O Nu-H R2 R1 N2 CH3 O O • In the prototypical case depicted below, the Wolff rearrangement proceeds in higher yield relative to the analogous Favorskii system O CH3 O O N2 (±)-Spatol h", CH3OH OCH3 > 99% Harmata, M.; Rashatasakhon, P Org Lett 2001, 3, 2533–2535 Tomioka, H.; Okuno, H.; Izawa, Y J Org Chem 1980, 45, 5278–5283 • The stereochemistry of the ! position can be kinetically controlled, determined by the relative rates of protonation of the enol or enolate intermediate H CH3 CH3 LAH KH O LAH CH3 H CH3 CH3 H+ CH3 CH3 Br OH 91% (3 steps) CH3 (±)-Sterpurene O h", CH3OH OH OCH3 N2 H+ H + CO2CH3 CO2CH3 H 92%, 88 : 12 Harmata, M.; Bohnert, G J Org Lett 2003, 5, 59–61 Kirmse, W.; Wroblowsky, H.-J Chem Ber 1983, 116, 1118–1131 Matt Mitcheltree Myers Chem 115 Methods for Ring Contraction Wolff Rearrangement Synthesis of diazo ketones • Ketene intermediates produced in the Wolff rearrangement can also be trapped in [2+2] cycloaddition reactions R CH3 CH3 O N2 O R O O O O h!, THF R' R' Review O O O O O [2+2] CH3 CH3 CH3 CH3 Stevens, R V.; Bisacchi, G S.; Goldsmith, L.; Strouse, C E J Org Chem 1980, 45, 2708–2709 Livinghouse, T.; Stevens, R V J Am Chem Soc 1978, 100, 6479–6482 O Doyle, M P.; McKervey, M A.; Ye, T Modern Catalytic Methods for Organic Synthesis with Diazo Compounds Wiley-Interscience, New York, 1998, pp 1–60 See course handout "C–O Bond-Forming Reactions" for further discussion of the synthesis of diazo compounds Direct Diazotization R' R' • Compounds such as 1,3-dicarbonyls can be diazotized directly using arenesulfonyl azide reagents R R' Yield H H 84% CH3 CH3 64% CH3 H 76% Ph H 54% O R' R O N3SO2Ar O O R Et3N R' N2 • In the absence of a " activating group, #-diazo ketones can be formed by formylation-diazotizationdeformylation, in a procedure known as Regitz diazo transfer • Danheiser and Helgason used such a strategy in the synthesis of salvilenone The [2+2] cycloadduct in this case underwent retro-[2+2] ring opening followed by electrocyclization N2 Br i-Pr O i-Pr h!, DCE O + CH3 H OTIPS 80 °C CH3 CH3 O HO CH3 Salvilenone N2 R R3N NaH OTIPS OTIPS Br Br O N3SO2Ar Regitz, M.; Maas, G Diazo Compounds, Academic Press, New York, 1986, pp 199–543 Regitz, M in: The Chemistry of Diazonium and Diazo Groups, Part (Ed.: Patai, S.), WileyInterscience, Chichester, 1978, pp 751–820 i-Pr i-Pr O OH H R retro [2+2] CH3 i-Pr O OR R Br OTIPS O O • Similarly, in the Danheiser procedure, reversible #$trifluoroacetylation activates the substrate toward diazotization O CH3 CH3 Danheiser, R L.; Helgason, A L J Am Chem Soc 1994, 116, 9471–9479 CF3 O O 61–71% CF3 O OH O R R LiHMDS CF3 O N3SO2Ar N2 R R3N Danheiser, R L.; Miller, R F.; Brisbois, R B.; Org Synth 1996, 73, 134–143 Danheiser, R L.; Miller, R F.; Brisbois, R G.; Park, S Z J Org Chem 1990, 55, 1959–1964 Matt Mitcheltree Myers Chem 115 Methods for Ring Contraction Synthesis of diazo ketones Wolff Rearrangement – Applications in target-oriented synthesis • In the Mandler procedure, enolized ketones are diazotized without the assistance of an activating group These reactions are generally run under phase-transfer conditions, and are therefore not ideal for substrates sensitive to aqueous base (e.g., esters) • Sequential Regitz diazotization–Wolff rearrangement was applied by Eaton and Nyi in their synthesis of [3.2.2]propellane Thermolytic decarboxylation of a tert-butyl perester provides the final product after ring contraction O N3SO2Mes (n-Bu)4NBr, KOH, 18-cr-6 R N3Tf Et2NH NaH HCO2Et O N2 R 1:1 H2O–C6H6 O O H O HO 85% Lombardo, L.; Mandler, L N Synthesis 1980, 368–369 h! CH3OH N2 95% NH2 TBSO O N N N Eaton, P E.; Nyi, K J Am Chem Soc 1971, 93, 2786–2788 N(CH3)2 CH3O CH3O H TBSO O (CH3)2N B N3Tf TBSO O O O O 72% 80% h! O + NaHMDS, HCO2Et N3Ts, Et3N h!, CH3OH LiOH N N NH2 HO OH N Oxetanocin Norbeck, D W.; Kramer, J B J Am Chem Soc 1988, 110, 7217–7218 O N2 62% (2 steps) 78% O 45% • Similarly, Corey and Mascitti use two Regitz diazotization–Wolff rearrangement reactions in sequence in their enantioselective synthesis of pentacycloannamoxic acid methyl ester B N2 O 60% t-BuOOH 160 °C • Mild conditions to activate cyclic ketones using dimethylformamide dimethyl acetal have been developed The resulting enamine intermediates undergo diazotization with electron-poor diazo transfer reagents such as triflyl azide (N3SO2CF3) This approach was used in the synthesis of oxetanocin, a bacterial isolate with anti-HIV activity N CO2CH3 Regitz h!, CH3OH N CHO H 43% (4 steps) O DIBAL-H Swern (CH2)7CO2CH3 CO2H 86% (2 steps) Pentacycloannamoxic acid methyl ester H Mascitti, V.; Corey, E J J Am Chem Soc 2006, 128, 3118–3119 Matt Mitcheltree Myers Chem 115 Methods for Ring Contraction Wolff Rearrangement – Applications in target-oriented synthesis Cation-type rearrangements • The Wolff rearrangement has been employed in the construction of the fused 5,5,5-tricyclic cores of sesquiterpenes Pinacol Rearrangement CH3 CH H CH3 O CH3 CH H CO2CH3 CH3 h", CH3OH H HO CH3 CH NaH, HCO2Et N3Ts, Et3N HO Reviews Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q Chem Rev 2011, 111, 7523–7556 Overman, L E.; Pennington, L D J Org Chem 2003, 68, 7143–7157 Overman, L E Acc Chem Res 1992, 25, 352–359 H CH3 H • Vicinal diols, when treated with acid, generate a transient cation that may undergo alkyl shift coupled with carbonyl formation H HO !9(12)-Capnellene 48% Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K J Chem Soc Perkin Trans 1992, 865–873 CH3 CH3 CH3 O H NaH, HCO2Et N3Ts, Et3N CH3O2C OH OH CH3 H+ CH3 OH O H CH3 CH3 CH3 –H+ –H2O CH3 68–72% CH3 h", CH3OH CH3 CH3 CH3 CH3 Pentalenene 83% Pavlik, C.; Morton, M D.; Smith, M B Synlett 2011, 2191–2194 CH3 CH3 H • Cationic rearrangements can proceed through concerted mechanisms as well, particularly when the migrating bond is aligned with the leaving group Ihara, M.; Katogi, M.; Fukumoto, K J Chem Soc Perkin Trans 1988, 2963–2970 • Where other methods failed, the Mandler procedure enabled Overman and co-workers to diazotize a ketone en route to (±)-meloscine N3SO2Ar (n-Bu)4NBr, 18-cr-6, KOH N BocHN BocHN 1:1 C6H6–H2O 35 °C, 1h OBn N2 98% N H CH3 CH3 • Halogens and sulfonate esters can also be used, as demonstrated below OBn H HO CO2CH3 CH3 O OTs Ph3P CH2 H CH3 H H H Al2O3 H N BocHN (±)-Meloscine H O OBn h", CH3OH O H2O Hariprakasha, H K.; SubbaRao, G S R Tetradron Lett 1997, 38, 5343–5346 O Ar = 2,4,6-triisopropylphenyl HN C6H6, reflux CH3O CH3 HO CH3 H F3B 90% H H O N BF3•OEt2 CH3O CH3 HO CH3 H CH3 H CH3 CH 100% CH3 H CH3 CH H CH3 53% (–)-Aromadendrene 95% Büchi, G.; Hofheinz, W.; Paukstelis, J V J Am Chem Soc 1969, 91, 6473–6478 Overman, L E.; Robertson, G M.; Robichaud, A J J Am Chem Soc 1991, 113, 2598–2610 Overman, L E.; Robertson, G M.; Robichaud, A J J Org Chem 1989, 54, 1236–1238 Matt Mitcheltree Myers Chem 115 Methods for Ring Contraction PInacol Rearrangement • Schreiber's synthesis of the bicyclic core of calicheamicin relied on a pinacol rearrangement Tautomerization of the resulting !-hydroxy ketone gave the enone product shown MsO TBSO LA H H OH OH H H O OH O H Et2AlCl TBSO • The reaction of epoxides with Lewis acids can provide ring-contracted products by a pinacol-type mechanism n Yield CHO LiBr, Al2O3 77% O 42% PhCH3 n n 30% TBSO OH CH2Cl2 Suga, H.; Miyake, H Synthesis 1988, 394–395 O O 65% BF3•OEt2 Schoenen, F J.; Porco, J A.; Schreiber, S L Tetrahedron Lett 1989, 30, 3765–3768 CH3 CH3 CHO O CH3 CH3 CH3 CH3 93% CH3S CH3 O I O CH3 O HO CH3O OH CH3 S OCH3 OH OCH3 HN O HO O CH3 S S O H O H Kunisch, F.; Hobert, K.; Weizel, P Tetrahedron Lett 1985, 26, 6039–6042 OH O HN O OCH3 • Yamamoto and co-workers have described an epoxide-opening ring contraction utilizing a methylaluminum diphenoxide Lewis acid that outperforms boron trifluoride in difficult ring contractions O EtHN CH3O CH3 Calicheamicin "1 CH3 CHO O MABR OTBS • Similarly, Paquette employed a pinacol rearrangement to produce the (+)-taxusin skeleton O CH3 CH3 CH3 HO OMs O Et2AlCl CH2Cl2–Hexane –78 # –15 °C AcO CH3 CH3 CH3 CH3 H O O 96% AcO CH3 OAc CH3 CH3 i-Pr MABR = CH3Al(OAr)2 82% OHC O CH2Cl2, –78 °C t-Bu CH3 MABR OTBS i-Pr H CH2Cl2, –78 °C i-Pr CH3 O OTBS Ar = OTBS Br t-Bu i-Pr 88% O (+)-Taxusin Maruoka, K.; Ooi, T.; Yamamoto, H J Am Chem Soc 1989, 111, 6431–6432 Paquette, L A.; Zhao, M J Am Chem Soc 1998, 120, 5203–5212 Matt Mitcheltree Myers • After cationic rearrangement, the resulting cation may be intercepted by elimination of an adjacent proton: Pinacol Rearrangement • Kuwajima and Baran both used pinacol-type rearrangements in their syntheses of ingenol TsO Kuwajima CH3 CH3 CH3 O CH3 CH3 H Al(CH3)3 OH CH2Cl2 CH3 H OTIPS OCH3 OCH3 OTIPS O OH HO CH3 CH3 CH3 O CH3O Baran CH3 CH3 CH3 CH3 TMS OTBS O O O O CH3 BF3•OEt2 CH3 CH3 CH3 O CH3 CH3 O 80% CH3 FeBr3 H LA CH3 CH3 O CH3 CH3 CH3 OH Ingenol CH3 O CH3 CrO2Cl2 CH3 • A tandem pinacol–Schmidt rearrangement was used to synthesize the core of (±)-stemonamine (–)-Solavetivone 71% TiCl4 TMSO N3 O OH O O N3 N3 CH2Cl2 –78 ! °C CH3 CH3 CH3 O N O Cl2 Ti O N2 N CH3 O OH CH3 CH3 (±)-Stemonamine MgI2 HN(TMS)2 OMs CH3 O OCH3 CH3 H CH3 54% • Or by attack with an endogenous nucleophile TMSO N t-BuOH H CH3 Hwu, J R.; Wetzel, J M J Org Chem 1992, 57, 922–928 Cl2 Ti O H CH3 Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I J Am Chem Soc 2003, 125, 1498–1500 Jørgensen, L.; McKerall, S J.; Kuttruff, C A.; Ungeheuer, F.; Felding, J.; Baran, P S Science 2013, 341, 878–882 CH3 CH3 TMS OH CH3 HO HO HO CH3 H 76% "-bulnesene OTBS O O H CH TMS –60 °C CH3 CH2Cl2 CH3 CH3 Heathcock, C H.; Ratcliffe, R J Am Chem Soc 1971, 93, 1746–1757 TMS CH3 H • By elimination of a #-silyl group: CH3 CH3 O CH3 CH3 AcOH, AcOK 80 °C, h OTIPS Al(CH3)3 CH3 CH3 H CH3 76% HO Chem 115 Methods for Ring Contraction H CH3 CH3 CH3 H CH3 CH3 TMSO H CH3 OHC CH3 CH3 H OHC CH3 H (+)-Isovelleral CH3 CH3 H O H 82% 68% Zhao, Y M.; Gu, P M.; Tu, Y Q.; Fan, C A.; Zhang, Q W Org Lett 2008, 10, 1763–1766 Bell, R P L.; Wjnberg, J B P A.; de Groot, A J Org Chem 2001, 66, 2350–2357 Matt Mitcheltree Myers Chem 115 Methods for Ring Contraction Lead-promoted ring contractions • An example of a pinacol rearrangement initiated by an endogenous electrophile was demonstrated by Oltra: O HO CH3 O CH3 O TMSCl, NaI H HO CH3 O • This reaction is believed to involve Pb–C bond formation followed by pinacol-type rearrangement CH3 CH3 O CH3 • Lead(IV) salts have been shown to promote ring contractions of ketones and enol ethers However, these reactions sometimes provide significant amounts of !-acetoxy ketone sideproducts O O TMS O H CH O CH3 CH3 O OH O O O Pb(OAc)4 OAc OAc O O OAc O H – Pb(OAc)3 –Pb(OAc)3 OAc > 72% Rosales, A.; Estévez, R E.; Cuerva, J M.; Oltra, J E Angew Chem., Int Ed 2005, 44, 319–322 • The Imamura synthesis of (–)-hyrtiosal employed an epoxide-opening rearrangement that is proposed to mimic the biosynthetic route to the natural product O CH3 CH3 RO CH3 CH3 R = (S)-mandeloyl • Lead(IV)-promoted ring contractions have been employed to modify !-santonin Improved yields were achieved by first converting the substrate to the corresponding ethyl-enol ether CHO CH3 CH3 H Norman, R O C.; Thomas, T B J Chem Soc B 1967, 604–611 BF3•OEt2 O C6H6 H RO Pb(OAc)4 BF3•OEt2 CH3 CH3 CH3 H O O CH3 CH3 CH3 O O CH3OH CH2Cl2 CH3O CH3 H O CH3 H CH3 O O Pb(OAc)4 BF3•OEt2, EtOH CH3 CH3 CH3 O 30% CH3 O H H HO H O HC(OEt)3 NH4Cl EtOH CHO CH3 H CH3 + CH3 67% !-Santonin 96% AcO H CH3 H CH3 O O CH3 CH3 (–)-Hyrtiosal Lunardi, I.; Santiago, G M P.; Imamura, P M Tetrahedron Lett 2002, 43, 3609–3611 EtO CH3 H CH3 O C6H6 EtO O O 100% CH3 CH3 H O 80% Miura, H.; Fujimoto, Y.; Tatsuno, T Synthesis 1979, 898–899 Matt Mitcheltree Myers Chem 115 Methods for Ring Contraction Ring contractions of silyl-enol ethers • Cyclic silyl-enol ethers undergo ring contraction upon treatment with electron-deficient sulfonyl azides to give trialkylsilyl imidates, which are readily hydrolyzed to N-acyl sulfonamides • Because alkyl migration is stereospecific, the stereochemistry of the product is determined by the facial selectivity of sulfonyl-azide addition Lesser facial differentiation leads to lower diastereomeric ratios, as the following series demonstrates • While both triflyl azide (N3Tf) and nonaflyl azide (N3Nf; N3SO2n-C4F9) may be used in the ring contraction of silyl-enol ethers, the latter has the advantage of being a bench-stable, non-volatile liquid that does not detonate spontaneously upon concentration N3Nf CH3 OSiR3 R3SiO N3SO2C4F9 R R3SiO Nf N H R CH3CN –N2 O N Nf H2O H N H • Alkyl, vinyl, and aryl migrations are all possible While 6!5 and 7!6 ring contractions are possible, this method does not permit cyclobutane synthesis Product OTMS CH3 CH3 O N3Nf single diastereomer NHNf d.r = 67 : 33 Yield OTMS O N3Nf O NHNf CH3 CH3 OTMS Substrate CH3 O NNf –N2 Nf R R TMSO OTMS NHNf d.r = 55 : 45 NHNf 97% CH3 CH3 • The resulting N-acyl sulfonamide can be converted to alcohol, ester, or carboxamide products OTMS O NHNf 67% OH LAH 85% O OTMS NHNf O 78% SO2C4F9 NH Et2O, 0!23 °C, 20 O OCH3 HCl (0.3 M) 75% O OTMS 20% CH3OH–PhCH3 110 °C, h NHNf 87% O NH2 SmI2 OTIPS 96% THF, 23 °C, 30 O NHNf H CH3 CH3 CH3 O O CH3 65% O Mitcheltree, M J.; Konst, Z A.; Herzon, S B Tetrahedron 2013, 69, 5634–5639 O CH3 CH Mitcheltree, M J.; Konst, Z A.; Herzon, S B Tetrahedron 2013, 69, 5634–5639 Matt Mitcheltree 10 Myers Chem 115 Methods for Ring Contraction Synthesis of regiodefined silyl-enol ethers • Silyl-enol ethers are appealing substrates for ring contractions because they can be synthesized regioselectively O OTMS CH3 Conditions CH3 • Silyl-enol ethers can be formed by enantioselective, catalytic Diels–Alder reactions H Ph O OTMS CH3 Br + TIPSO A Conditions Yield A:B LDA, TMSCl 74 99 : Et3N, TMSCl, NaI 92 10 : 90 CH3 H N B o-Tol CH3 O B Ph O TIPSO HNTf2 –78 °C CH3 O Br CH3 O 96%, 97% e.e Ryu, D H.; Zhou, G.; Corey, E J J Am Chem Soc 2004, 126, 4800–4802 Negishi, E.-I.; Chatterjee, S Tetrahedron Lett 1983, 24, 1341–1344 House, H O.; Czuba, L J.; Gall, M.; Olmstead, H D J Org Chem 1969, 34, 2324–2336 • Silyl-enol ethers can also be formed by 1,4-addition to !,"-unsaturated carbonyls CH3 O CH3 CH3 OTBS OTMS MgBr CH3 CuBr•S(CH3)2 TMEDA, TMSCl TBSO CH3 CH3 100% Nozawa, D.; Takikawa, H.; Mori, K J Chem Soc Perkin Trans 1, 2000, 2043–2046 • Birch reduction of substituted silyloxy aryl ethers gives regiodefined substrates for ring contraction OTES OTES Li, NH3 i-Pr t-BuOH, THF i-Pr 90% Macdonald, T L J Org Chem 1978, 18, 3621–3624 Matt Mitcheltree 11 ... 1979, 898–899 Matt Mitcheltree Myers Chem 115 Methods for Ring Contraction Ring contractions of silyl-enol ethers • Cyclic silyl-enol ethers undergo ring contraction upon treatment with electron-deficient... Matt Mitcheltree 10 Myers Chem 115 Methods for Ring Contraction Synthesis of regiodefined silyl-enol ethers • Silyl-enol ethers are appealing substrates for ring contractions because they can be... Org Chem 1988, 53, 4877–4883 Matt Mitcheltree Myers Chem 115 Methods for Ring Contraction Quasi-Favorskii Rearrangement Carbenoid Ring Contractions • Harmata has showcased the power of the quasi-Favorskii