Myers Cyclobutane Synthesis Chem 115 Reviews: • Intramolecular [2+2] Cycloadditions: Hoffmann, N. Chem. Rev. 2008, 108, 1052–1103. • Intramolecular [2+2] cycloadducts are readily formed. Tethers are typically 2 to 4 atom: Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449–1484. Crimmins, M. T. Chem. Rev. 1988, 88, 1453–1473. Bach, T. Synthesis 1998, 683–703. H C O CH3 3 h$ O * Challenges: O hexanes OBz • Cyclobutanes are highly strained: H C OBz 98%, dr = 92:8 3 H OBz minimize non-bonded interactions 1. LHMDS Strain energy in kcal/mol 27.5 26.3 6.2 0.1 MeI (2 equiv) H C CH THF 3 3 CH H3C H3C CH3 3 O –70 " 0 ºC H BF •Et O H3C CH3 H3C 3 2 6 steps H Wiberg, K. B. Angew. Chem. Int. Ed. 1986, 25, 312–322. • 2. KOH, DMSO • 25 ºC, 36% C6H6, 80 °C CH 50% H Synthetic Methods For the Construction of Cyclobutanes: 3 H C H 3 O • [2+2] Cycloadditions: #8,9-capnellene epi-precapnelladiene • Suprafacial [2+2] cycloadditions are photochemically allowed but thermally forbidden. • Frontier Molecular Orbital Analysis: Birch, A. M.; Pattenden, G. J. Chem. Soc., Chem. Commun. 1980, 1195–1197. Birch, A. M.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1, 1983, 1913–1917. • Intermolecular [2+2] Cycloadditions • Regioselectivity issues: head-to-tail (HT) vs. head-to-head (HH) Thermal Photochemical LUMO of one ethylene unit !* !* O O O X h$ R HOMO of one ethylene unit ! !* one ethylene unit is photoexcited R R suprafacial [2+2] suprafacial [2+2] symmetry forbidden symmetry allowed HT HH • Enones are generally used as they are more easily photoexcited than isolated olefins. • Generally: • Photoexcited enones react via the T1 (triplet excited state). HT-isomer favored when R = donor (electron donating) • Quantum efficiencies are higher in cyclic systems due to rapid intersystem crossing. HH-isomer favored when R = acceptor (electron withdrawing) • Acyclic and macrocyclic enones are typically not suitable for [2+2] photocycloaddition because upon photoexcitation, they undergo cis/trans isomerization. Danica Rankic 1 Myers Cyclobutane Synthesis Chem 115 • An Example of Regioselectivity Governed by Electronics • Ketene [2+2] Cycloadditions • Antarafacial [2+2] cycloadditions are thermally allowed but geometrically disfavored for most substrates. O O O h! H H R • Ketenes are linear and sterically less encumbered, making them good substrates for thermal [2+2] HN HN HN * cycloadditions. H3C H3C * H3C R R • Frontier Molecular Orbital Analysis: H3C H3C H H3C H HH HT R d.r. (HT : HH) O C CN 18 : 82 C O C OEt 95 : 5 C • Both HT and HH products were obtained as a mixture of two diastereomers. LUMO HOMO Suishu, T.; Shimo, T.; Somekawa, K. Tetrahedron 1997, 53, 3545–3556. of C=C=O of C=C ketene alkene • Stereoselectivity in Intermolecular [2+2] Cycloadditions • The least hindered transition state usually dominates. There is no "endo" effect, as in the Diels- • Ketenes can be generated in situ from acid chlorides: Alder Reaction: CH O CH O CH 3 3 H CH CH 3 H3CO2C CO2CH3 CH3 3 3 h!, CH2Cl2 NEt3, CH2Cl2 H C H C 3 + 3 O Cl O + O 23 ºC, 49% 40 ºC, 70% CH CH O O O 3 CH H 3 H H 3 CH3 CH3 HO H 3.4 : 1 (separable by chromatography) (+)-grandisol Wilson, S. R.; Phillips, L. R.; Pelister, Y.; Huffman, J. C. J. Am. Chem. Soc. 1979, 101, 7373–7379. • When the double bond is not constrained within a rigid ring system, the intermediate triplet state Mori, K.; Miyake, M. Tetrahedron 1987, 43, 2229–2239. diradical can lead to cis/trans isomerization of the double bond: H C 3 h!, pentane + H3C 23 ºC, 73% H CH3 H3C Cl H C H C Zn, POCl3 O 3 Cl3C Cl + 3 Cl O Et O, 40 ºC H3C H 2 O H3C H H CH O 78% 3 h!, pentane O mixture of cis and + trans isomers H3C 23 ºC, 63% O Krepski, L. R.; Hassner, A. J. Org. Chem. 1978, 43, 2879–2882. Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc. 1964, 86, 5570–5583. Danica Rankic, Fan Liu 2 Myers Cyclobutane Synthesis Chem 115 • Examples of [2+2] Cycloaddition in Synthesis • A [2+2] Cycloaddition followed by radical fragmentation provided a key intermediate to guanacastepene E: • Synthesis of pentacycloanammoxic acid, the principal lipid component of the cell membrane of O PMP the anaerobic microbe Candidatus Brocadia anammoxidans: O O O O PMP h!, i-Pr2NEt O O Et O, 82% 1. (COCl)2, DMF i-Pr CH3 CH 2 i-Pr CH 3 H3C 3 h!, MeCN 4 steps CH Cl , 23 ºC O 2 2 1. SmI2, HMPA –15 ºC, 78 ºC 2. Br CO2H THF, 23 ºC 2. PhSeBr, 50% N S 3. mCPBA, CH2Cl2 ONa t-BuOK –78 ºC, 86% BrCCl3, 75 ºC, DMSO O O O PMP DMAP 50 ºC, 84% H OH 5 steps O h!, 10 ºC, 79% AcO O O i-Pr CH3 CH3 i-Pr H C CH3 guanacastepene E 3 12 steps Si(CH ) Ph Shipe, W. D.; Sorensen, E. J. J. Am. Chem. Soc. 2006, 128, 7025–7035. O 3 2 • A late-stage coupling reaction provided access to biyouyanagin A: h!, MeCN (CH2)7CO2CH3 23 ºC, 50% Ph(H3C)2Si pentacycloanammoxic acid H H C H H C CH 3 CH CH 3 3 CH H 3 O 3 H H H O 3 Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 3118–3119. CH3 h!, CH2Cl2 CH3 • A [2+2] cycloaddition/anionic oxy-Cope/electrocyclic ring opening cascade provided a key O O Ph O 2'-acetonaphthone O intermediate to periplanone B. Note that both diastereomers from the [2+2] cycloaddition step can H Ph CH O 25 ºC, 46% H C O be converted to the final product: 3 3 O 1. Et O, Nicolaou, K. C.; Sarlah, D.; Shaw, D. M. Angew. Chem. Int. Ed. 2007, 46, 4708–4711. O 2 MgBr CH3 h!, Et2O –78 ºC, 63% • A [2+2] photocycloaddition followed by acid-catalyzed rearrangement provided a key intermediate H CH3 to steviol: CH3 72%, dr = 2:1 2. KH, 18-C-6 H CH3 THF, 60 ºC O H C CH h!, CH Cl 2 • 2 75% H3C 2 2 H3C CH O 23 ºC, 82% HO 3 1. O3, MeOH CH3 HO –78 ºC H2C CH2 2. Me S, 23 ºC O O • 2 1. toluene, 175 ºC 3. AcOH, PPA 110 ºC, 62% CH3 CH3 H C 2. C6H6, h! 3 O CH 70–75% CH 3 3 HO CH3 O Schreiber, S. L.; Santini, C. J. Am. Chem. Soc. 1984, 106, 4038–4039. Cherney, E. C.; Green, J. C.; Baran, P. S. Angew. Chem. Int. Ed. 2013, 52, 9019–9022. Fan Liu 3 Myers Cyclobutane Synthesis Chem 115 • The synthesis of longifolene was accomplished via a de Mayo reaction –– a [2+2] cycloaddition • In the synthesis of ginkgolide B, three contiguous stereogenic centers were established using an followed by retro-Aldol fragmentation: intramolecular ketene [2+2] cycloaddition reaction: H3CO O O O O OCbz OCbz 1. (COCl)2, C6H6 O h", C6H12 H2, Pd/C 23 ºC Ph3C OH H 15–30 ºC, 83% AcOH, 25 ºC 2. n-Bu3N, toluene 1N NaOH H H H H O dr = 2:3 O 83% 110 ºC, 71–87% acetone O O O CO2H O –30 ºC, 86% H3C PPh3 steps – O Br HO H3C NaOt-amyl OH CH3 H O toluene, 25 ºC O 4 steps 88% O H O t-Bu H C H HO H 3 H3C O O O Longifolene Ginkgolide B Corey, E. J.; Kang, M.-C.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988, 110, 649– Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583–2584. 651. • Synthesis of clovene via a ketene [2+2] thermal cycloaddition: • Synthesis of retigeranic acid via a ketene [2+2] cycloaddition followed by cyclobutane ring expansion: 1. Li H3C CH3 H3C N Cl H3C H H3C SCH3 CO H H O H3CS 2 1. (COCl)2, C6H6, 23 ºC CH3 CH SCH H 3 3 H CH3 SMe 2. Et N, 23 ºC, 80 % H Et3N, CH3CN O THF, –78 ºC 3 CO2H SMe H H 80 ºC, 35–47% H3C 2. HCl, CHCl3 H C O CH3 3 CH 66% 3 1. Li 1. NaH, MeI, SCH H3C 3 DME, 75% SCH3 2. Raney Ni, H C THF, –78 ºC CH3 3 H acetone, 79% H3C H H3C H CH 73% CH3 1. H2NNHTs, MeOH CH 5 steps 3 H H 3 H H 2. CuOTf, Et3N H C H 3 2. BuLi, TMEDA; H C C6H6, 23 ºC 3 O H3C + H CH3 H 3. NaIO , H O H3O , 55% H3C CO H 4 2 O H3C 2 H3C clovene CH3 CH3 dioxane Bamford-Stevens-Shapiro Reaction 4. Al/Hg, THF retigeranic acid H2O, 0 ! 23 ºC Funk, R. L.; Novak, P. M.; Abelman, M. M. Tetrahedron Lett. 1988, 29, 1493–1496. Corey, E. J.; Desaid, M.; Engler, T. A. J. Am. Chem. Soc. 1985, 107, 4339–4341. Fan Liu 4 Myers Cyclobutane Synthesis Chem 115 • Formal [2+2] Cycloadditions: Michael-Aldol Mechanism • Upon activation by triflic anhydride, C2-symmetric chiral pyrrolidine amides form keteniminium • Silyl enol ethers and !,"-unsaturated compounds form cyclobutanes in a stepwise, Lewis acid- salts, which undergo thermal [2+2] cycloadditions with excellent stereoselectivities: catalyzed process. • In the following example, the bulky tris(trimethylsilyl)silyl (TTMSS) protecting group is required to stabilize the cationic intermediate.