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 Favorskii Rearrangement 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 alkyl 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 Wolff Rearrangement 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 !-diazo ketone via carbene or O Cl O carbenoid to a ketene, 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. Matt Mitcheltree 3 Myers Methods for Ring Contraction Chem 115 Wolff Rearrangement Synthesis of diazo ketones • 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 azide 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 4 Myers Methods for Ring Contraction Chem 115 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., esters). 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.