Myers Methods for Ring Contraction Chem 115

Recent Reviews: • Chiral-pool starting materials have been much used as substrates for the Favorskii reaction, affording functionalized, optically active cyclopentanes. Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556. O O O Silva, Jr. L. F. Tetrahedron 2002, 58, 9137–9161. H O Cl CH3 2 2 CH 1. TMSCl 3 CH3 • O Ring contraction reactions can be grouped into three general categories based on mechanism: NaOH 2. DHP, p-TsOH THPO 90% 81% (2 steps) O O Nu CH3 CH3 CH3 X Nu: Anionic (–)-Carvone NaOCH3 CH3OH

O Nu O O CH CO3CH3 3 CH H Nu: 3 CH Carbenoid THPO 3 80% CH3 THPO

M Lee, E.; Yoon, C. H. J. Chem. Soc., Chem. Commun. 1994, 479–481. O O R R • For example, the ring contraction of a (+)-pulegone derivative has been used in the synthesis of Cationic several terpenoid natural products.

CH CH3 3 CH3 Anionic Ring Contractions Br2 NaOCH3 CO2CH3 O O Et2O Br CH3OH • The Favorskii reaction leads to the rearrangement of an !-halo cycloalkanone upon treatment CH3 CH3 CH3 CH3 CH3 Br with base. This reaction proceeds through a cyclopropanone intermediate that is opened by CH3 60–67% (2 steps) nucleophilic attack. (+)-Pulegone

O O O OCH3 NaOCH OCH3 Cl 3

Et2O, 35 °C, 2 h

CH CH3 56–61% CH 3 3 H CH3 H Organic syntheses; Wiley & Sons: New York, 1963; Coll. Vol. No. 4, pp. 594. CH CH3 3 O H O CH3 CH • In some cases, enolization is not possible, precluding cyclopropanone formation. An alternate O 3 H H CH3 mechanism involves formation of a tetrahedral intermediate that promotes migration. CH3 (+)-Epoxydictymene (–)-Iridomyrmecin (+)-Acoradiene + Br Ag Br CO2H AgNO3 Common intermediate: Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel's OH O Textbook of Practical Organic Chemistry. 5th ed. Longman: London, 1989. H O, t-BuOH 2 OH (+)-Epoxydictymene: Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. H H H Soc. 1997, 119, 4353–4363. 71% (–)-Iridomyrmecin: Wolinsky, J.; Gibson, T.; Chan, D.; Wolf, H. Tetrahedron 1965, 21, 1247–1261. Cope, A. C.; Graham, E. S. J. Am. Chem. Soc. 1951, 73, 4702–4706. (+)-Acoradiene: Kurosawa, S.; Bando, M.; Mori, K. Eur. J. Org. Chem. 2001, 4395–4399. Loftfield, R. B. J. Am. Chem. Soc. 1951, 73, 4707–4714. Matt Mitcheltree

1 Myers Methods for Ring Contraction Chem 115

Quasi-Favorskii Rearrangement • A common application of the quasi-Favorskii rearrangement is in the rearrangement of fused • Also referred to as the negative-ion pinacol rearrangement, the quasi-Favorskii rearrangement polycycles. involves an alkyl shift with concomitant nucleophilic displacement of an aligned leaving group. OH OMs O • These fragmentations are generally accelerated by oxyanion formation. HO 1. MsCl (1 equiv), pyr O CH 2. KOt-Bu 3 H CH CH3 HO CH3 3 O CH3 O OTs KOt-Bu CH 60% (2 steps) 3 CH OTs + 3 THF O 90%, 89 : 11 Hamon, D. P. G.; Tuck, K. L. Chem. Commun. 1997, 941–942.

CH3 OH HO CHO CH3 Br LAH Br CH3 H CH3 O O H H H H Marshall, J. A.; Brady, S. F. J. Org. Chem. 1970, 35, 4068–4077. (±)-Hinesol

98%

Harmata, M.; Bohnert, G.; Kürti, L.; Barnes, C. L. Tetrahedron Lett. 2002, 43, 2347–2349. CH OH OH CH3 3 CH3 O LiOH O O O H • A quasi-Favorskii ring contraction was employed by Harding in the synthesis of (±)-sirenin. The O O stereochemical outcome of this rearrangement suggests formation of a tetrahedral intermediate t-BuOH, 65 °C O H O HO that undergoes alkyl shift with halide displacement, rather than cyclopropanone formation as in OTs OTs O the classic Favorskii rearrangement. 87%

H O CH3O OH H AgNO3 CH3 Cl CH OH Cl OBn CH O C CH 3 3 2 3 H CH3H H OBn Ag+ OBn O CH3 O 53% O

H CH3 O H (±)-Confertin CH3 Heathcock, C. H.; DelMar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907–1917. OBn CH CH3 H 3 HO H OH (±)-Sirenin

Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org. Chem. 1988, 53, 4877–4883. Matt Mitcheltree

2 Myers Methods for Ring Contraction Chem 115

Quasi-Favorskii Rearrangement Carbenoid Ring Contractions

• Harmata has showcased the power of the quasi-Favorskii rearrangement in the synthesis of several terpenoid natural products. Reviews:

Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256. 1. LAH Meier, H.; Zeller, K.-P. Angew. Chem. Int. Ed. 1975, 14, 32–43. 2. KH H Cl CHO • The Wolff rearrangement involves the transformation of an !- via or O Cl O carbenoid to a , which undergoes further transformation to form a stable adduct. Stereochemistry 76% (2 steps) established by X-ray • The Wolff rearrangement may be induced by heat, Ag(I) salts, or light.

h", #, O O or AgI O Nu-H O Nu R2 R1 R2 R1 1 2 R1 R2 N2 R R CH3

H H Nu = -OCH3, -OBn, -OH, -NR2, SR, etc. H CH3 OH • In the prototypical case depicted below, the Wolff rearrangement proceeds in higher yield relative to the analogous Favorskii system. O O

CH3 CH3 O O OCH3 h", CH3OH N2 (±)-Spatol

> 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. CH H 1. LAH H 3 2. KH CH CH + 3 O 3 CH3 H CH3 CH3 CH3 3. LAH O h", CH3OH CH OH Br OH 3 H + CO2CH3 N2 OCH3 91% (3 steps) (±)-Sterpurene CO2CH3 H H+ 92%, 88 : 12

Kirmse, W.; Wroblowsky, H.-J. Chem. Ber. 1983, 116, 1118–1131. Harmata, M.; Bohnert, G. J. Org. Lett. 2003, 5, 59–61.

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3 Myers Methods for Ring Contraction Chem 115

Wolff Rearrangement Synthesis of diazo

• Ketene intermediates produced in the Wolff rearrangement can also be trapped in [2+2] Review cycloaddition reactions. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo R Compounds. Wiley-Interscience, New York, 1998, pp. 1–60. CH CH3 O 3 N2 See course handout "C–O Bond-Forming Reactions" for further discussion of the synthesis of diazo O O O R O O h!, THF R' R' compounds.

O O O O [2+2] O O Direct Diazotization CH3 CH3 CH3 CH3 R' R' • Compounds such as 1,3-dicarbonyls can be diazotized directly using arenesulfonyl reagents. R R' Yield

O O Stevens, R. V.; Bisacchi, G. S.; Goldsmith, L.; Strouse, H H 84% O O N3SO2Ar C. E. J. Org. Chem. 1980, 45, 2708–2709. CH CH 64% R R' 3 3 R R' Et3N N2 Livinghouse, T.; Stevens, R. V. J. Am. Chem. Soc. CH3 H 76% 1978, 100, 6479–6482. Ph H 54% • In the absence of a " activating group, #-diazo ketones can be formed by formylation-diazotization- deformylation, 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.

O i-Pr O O OH N2 O O i-Pr H OR N3SO2Ar N Br h!, DCE O OTIPS H 2 + Br R R R NaH R N 80 °C retro 3 OTIPS [2+2] CH3 CH3 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 2 (Ed.: Patai, S.), Wiley- Interscience, Chichester, 1978, pp. 751–820. i-Pr i-Pr i-Pr O O HO OTIPS OTIPS CH3 O • Similarly, in the Danheiser procedure, reversible #$trifluoroacetylation activates the substrate toward Br Br CH3 diazotization.

CH3 CH CH3 3 O CF3 Salvilenone 61–71% O O OH O CF3 O N SO Ar N CF 3 2 2 R R 3 R Danheiser, R. L.; Helgason, A. L. J. Am. Chem. Soc. 1994, 116, 9471–9479. LiHMDS 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

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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 • Sequential Regitz diazotization–Wolff rearrangement was applied by Eaton and Nyi in their group. These reactions are generally run under phase-transfer conditions, and are therefore not synthesis of [3.2.2]propellane. Thermolytic decarboxylation of a tert-butyl perester provides the ideal for substrates sensitive to aqueous base (e.g., ). final product after ring contraction.

NaH N3Tf h! O N3SO2Mes O HCO2Et Et2NH CH3OH (n-Bu)4NBr, KOH, 18-cr-6 N2 R R 1:1 H O–C H H N 2 6 6 O O O 2 CO CH HO 2 3 Lombardo, L.; Mandler, L. N. Synthesis 1980, 368–369. 85% 95% 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.

NH2 Eaton, P. E.; Nyi, K. J. Am. Chem. Soc. 1971, 93, 2786–2788. 45% N(CH3)2 N N CH3O TBSO H B • Similarly, Corey and Mascitti use two Regitz diazotization–Wolff rearrangement reactions in TBSO CH O O N Tf TBSO N 3 3 B O N O sequence in their enantioselective synthesis of pentacycloannamoxic acid methyl . (CH ) N 3 2 O O 1. NaHMDS, HCO2Et N2 O O h! O 2. N3Ts, Et3N O 80% 72% +

N2 78% 62% (2 steps)

1. h!, CH3OH O N 2. LiOH N NH2 HO 1. Regitz N N 2. h!, CH3OH OH O CHO CO H 3. DIBAL-H 2 Oxetanocin H 4. Swern Norbeck, D. W.; Kramer, J. B. J. Am. Chem. Soc. 1988, 110, 7217–7218. 43% (4 steps) 86% (2 steps)

(CH2)7CO2CH3 Pentacycloannamoxic acid methyl ester H

Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 3118–3119. Matt Mitcheltree

5 Myers Methods for Ring Contraction Chem 115

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 Pinacol Rearrangement of sesquiterpenes. Reviews Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556. CH3 CH CH CH 3 O 1. NaH, HCO Et 3 CH3 3 CH3 Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143–7157. H 2 H CO2CH3 H 2. N3Ts, Et3N Overman, L. E. Acc. Chem. Res. 1992, 25, 352–359.

CH 3 3. h", CH3OH CH3 CH3 • Vicinal diols, when treated with acid, generate a transient cation that may undergo alkyl shift HO H H H HO HO coupled with carbonyl formation.

48% !9(12)-Capnellene OH OH O CH Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 CH 3 CH3 H+ 3 1992, 865–873. OH CH3 CH3 CH3 + –H2O –H 1. NaH, HCO2Et CH3O2C CH CH3 3 O 2. N3Ts, Et3N 68–72% CH3 CH 3 CH3 Pavlik, C.; Morton, M. D.; Smith, M. B. Synlett 2011, 2191–2194. CH3 3. h", CH OH 3 H CH3 H CH3 H CH3 CH3 83% Pentalenene • 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. 1 1988, 2963–2970.

BF3•OEt2 CH H2O • Where other methods failed, the Mandler procedure enabled Overman and co-workers to CH O CH3 CH O 3 3 3 O H diazotize a ketone en route to (±)-meloscine. HO HO CH C6H6, reflux CH 3 H F B 3 H H N 3 CH CH3 N N3SO2Ar 3 BocHN BocHN (n-Bu)4NBr, 18-cr-6, KOH 90% H H 1:1 C H –H O Hariprakasha, H. K.; SubbaRao, G. S. R. Tetradron Lett. 1997, 38, 5343–5346. O 6 6 2 O OBn 35 °C, 1h OBn N2 Ar = 2,4,6-triisopropylphenyl 98% • Halogens and sulfonate esters can also be used, as demonstrated below.

O h", CH OH OTs 3 HO H H Al2O3 Ph3P CH2 N H N H H BocHN H CH3 H CH3 CH3 H CH3 CH CH3 OBn CH3 3 CH3 CH3 HN H 100% 53% CO2CH3 O (–)-Aromadendrene (±)-Meloscine 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

6 Myers Methods for Ring Contraction Chem 115

PInacol Rearrangement

• Schreiber's synthesis of the bicyclic core of calicheamicin relied on a pinacol rearrangement. • The reaction of epoxides with Lewis acids can provide ring-contracted products by a pinacol-type Tautomerization of the resulting !-hydroxy ketone gave the enone product shown. mechanism. n Yield CHO LiBr, Al O 2 3 1 77% O MsO LA H H H PhCH 2 42% H O OH n 3 H n O Et2AlCl 3 30% TBSO OH TBSO OH TBSO OH CH2Cl2 Suga, H.; Miyake, H. Synthesis 1988, 394–395.

O O 65% BF3•OEt2 CHO

Schoenen, F. J.; Porco, J. A.; Schreiber, S. L. Tetrahedron Lett. 1989, 30, 3765–3768. O CH3 CH3 CH CH 3 CH3 3 CH3 93%

H CH3S H Kunisch, F.; Hobert, K.; Weizel, P. Tetrahedron Lett. 1985, 26, 6039–6042. S OH CH3 O S CH CH3 O I 3 HN O S O O O HO HN OCH3 • Yamamoto and co-workers have described an epoxide-opening ring contraction utilizing a O O methylaluminum diphenoxide Lewis acid that outperforms boron trifluoride in difficult ring O OCH3 OH contractions. CH3 O OCH3 EtHN HO CH3O CH O 3 OH CH3 CH3 CHO Calicheamicin "1 O MABR OTBS

CH2Cl2, –78 °C MABR = CH3Al(OAr)2 OTBS i-Pr i-Pr • Similarly, Paquette employed a pinacol rearrangement to produce the (+)-taxusin skeleton. 82% t-Bu

Ar = Br CH3 OHC CH3 O MABR O O OTBS AcO OAc t-Bu CH CH3 3 CH3 CH Et2AlCl CH2Cl2, –78 °C 3 CH3 CH OTBS i-Pr CH CH3 3 3 CH Cl –Hexane i-Pr 2 2 CH3 88% H CH3 –78 # –15 °C H HO OMs O O AcO O O 96% (+)-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

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Pinacol Rearrangement • After cationic rearrangement, the resulting cation may be intercepted by elimination of an adjacent proton: • Kuwajima and Baran both used pinacol-type rearrangements in their syntheses of ingenol. CH Kuwajima TsO 3 CH3 CH3 CH3 AcOH, AcOK CH3 CH3 CH3 CH3 H CH3 HO CH OCH O 80 °C, 8 h 3 Al(CH ) 3 CH3 OH 3 3 OTIPS H H O CH3 H CH CH CH3 3 H H 3 CH3 CH CH2Cl2 CH3 3 O OH 76% OTIPS CH3O OCH3 OTIPS Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746–1757. "-bulnesene Al(CH3)3 76% • By elimination of a #-silyl group:

TMS Baran TMS CH CH3 CH CH3 CH 3 TMS CH 3 3 FeBr3 3 CH3 CH CH3 3 CH3 CH CH O O 3 3 CH3 O –60 °C CH LA 3 OH H CH CH3 H HO BF3•OEt2 CH3 CH 3 O TMS 3 CH3 CH3 O OTBS OTBS CH3 CH Cl O O 2 2 HO HO O CH O 3 O CH3 HO OH

80% Ingenol O CH3 CH3

Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. CrO2Cl2 Am. Chem. Soc. 2003, 125, 1498–1500. Jørgensen, L.; McKerall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. Science CH3 H t-BuOH CH3 H

2013, 341, 878–882. CH3 CH3 • A tandem pinacol–Schmidt rearrangement was used to synthesize the core of (±)-stemonamine. (–)-Solavetivone 71% 54% Hwu, J. R.; Wetzel, J. M. J. Org. Chem. 1992, 57, 922–928. Cl2 CH3 Ti • Or by attack with an endogenous . TiCl O N TMSO 4 O O OH 3 N3 MgI N3 CH Cl OMs 2 CH3 O 2 2 CH3 HN(TMS)2 –78 ! 0 °C CH3 CH 3 CH3 H CH3 CH TMSO 3 CH3 H TMSO H

O Cl2 Ti CH CH N O N 3 3 N O 2 OCH3 OHC N CH3 CH3 CH H H 3 CH3 CH3 O OHC O CH OH H H 3 O CH3 CH3 (+)-Isovelleral 82% (±)-Stemonamine 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

8 Myers Methods for Ring Contraction Chem 115

Lead-promoted ring contractions • An example of a pinacol rearrangement initiated by an endogenous electrophile was • Lead(IV) salts have been shown to promote ring contractions of ketones and enol ethers. demonstrated by Oltra: However, these reactions sometimes provide significant amounts of !-acetoxy ketone side- products.

O HO CH3 O TMSCl, • This reaction is believed to involve Pb–C bond formation followed by pinacol-type rearrangement. CH3 CH3 NaI H CH HO CH3 H O 3 O OAc CH CH3 O Pb(OAc) O OAc OAc O 3 O O 4 O O O O CH TMS O CH3 O H OAc 3 OH –Pb(OAc) – O Pb(OAc)3 3 > 72%

Rosales, A.; Estévez, R. E.; Cuerva, J. M.; Oltra, J. E. Angew. Chem., Int. Ed. 2005, 44, 319–322. Norman, R. O. C.; Thomas, T. B. J. Chem. Soc. B. 1967, 604–611.

• The Imamura synthesis of (–)-hyrtiosal employed an epoxide-opening rearrangement that is • Lead(IV)-promoted ring contractions have been employed to modify !-santonin. Improved yields proposed to mimic the biosynthetic route to the natural product. were achieved by first converting the substrate to the corresponding ethyl-enol ether.

O CHO CH CH Pb(OAc)4 3 CH3 3 CH3 CH3 BF •OEt O AcO CH3 CH3 BF •OEt CH3 CH3 3 2 3 2 H H + H H H O CH3 CH OH CH3O CH3 O CH3 O C6H6 O H 3 H H RO RO O CH CH3 CH2Cl2 3 O CH3 O CH3 CH3 CH3 CH3 O O O -Santonin 67% 30% R = (S)-mandeloyl 96% !

HC(OEt)3 NH4Cl EtOH CHO CH3 Pb(OAc)4 CH CH3 CH3 CH3 3 BF3•OEt2, EtOH O H H H O EtO HO EtO CH3 C6H6 CH3 H H CH3 CH3 CH3 CH3 O O O O (–)-Hyrtiosal 100% 80%

Lunardi, I.; Santiago, G. M. P.; Imamura, P. M. Tetrahedron Lett. 2002, 43, 3609–3611. Miura, H.; Fujimoto, Y.; Tatsuno, T. Synthesis 1979, 898–899.

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Ring contractions of silyl-enol ethers • Cyclic silyl-enol ethers undergo ring contraction upon treatment with electron-deficient sulfonyl • Because alkyl migration is stereospecific, the stereochemistry of the product is determined by to give trialkylsilyl imidates, which are readily hydrolyzed to N-acyl sulfonamides. 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 O liquid that does not detonate spontaneously upon concentration. OTMS TMSO NHNf NNf CH N Nf CH 3 3 3 CH3 OSiR 3 Nf R3SiO O H R3SiO N N N3SO2C4F9 N H O –N CH Nf 2 Nf 2 3 H H R CH CH single R R 3 3 CH3CN R diastereomer –N 2 O OTMS NHNf N3Nf • Alkyl, vinyl, and aryl migrations are all possible. While 6!5 and 7!6 ring contractions are d.r. = 67 : 33 possible, this method does not permit cyclobutane synthesis.

Substrate Product Yield OTMS O N Nf NHNf O 3 OTMS NHNf d.r. = 55 : 45 97% CH CH3 3

• The resulting N-acyl sulfonamide can be converted to , ester, or carboxamide products. OTMS O

NHNf 67% OH LAH 85% O Et2O, 0!23 °C, 20 min OTMS SO C F NHNf O 2 4 9 NH O 78% OCH3 HCl (0.3 M) 75% O 20% CH3OH–PhCH3 OTMS NHNf 110 °C, 3 h O 87% NH2 SmI2 96% THF, 23 °C, 30 min O OTIPS NHNf H Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634–5639. 65% CH3 O CH3 O O O CH3 CH CH 3 3 CH3

Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634–5639. Matt Mitcheltree

10 Myers Methods for Ring Contraction Chem 115

Synthesis of regiodefined silyl-enol ethers • Silyl-enol ethers are appealing substrates for ring contractions because they can be synthesized • Silyl-enol ethers can be formed by enantioselective, catalytic Diels–Alder reactions. regioselectively. H Ph Ph O OTMS OTMS O O O H N CH3 Conditions CH3 CH3 Br B Br + o-Tol TIPSO CH3 CH3 TIPSO CH3 CH3 A B O HNTf2 O –78 °C Conditions Yield A : B 96%, 97% e.e. LDA, TMSCl 74 99 : 1 Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800–4802.

Et3N, TMSCl, NaI 92 10 : 90

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.

CH O 3 OTMS MgBr CH3 CH3

CH3 CuBr•S(CH3)2 CH CH 3 OTBS TMEDA, TMSCl TBSO 3 100%

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.

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