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. This and the use of a bulky aluminum catalyst with the triflimide counterion suppress silyl transfer: H3C O CH3 N 1. 20 83 ºC H O N Tf2O, DTBMP C # Ph – CH ClCH CH Cl TfO 3 H3C 2 2 2. H2O, CCl4 O AlNTf )2 2 80 ºC, 88% H O O Ph (1 mol%) 98% ee TTMSSO TTMSSO OPh OPh CH2Cl2, –40 ºC 82%, dr = 10:1 Chen, L.; Ghosez, L. Tetrahedron Lett. 1990, 31, 4467–4470.

LA LA • (–)-Phenylmenthol was also found to be an effective chiral auxiliary in formal [2+2] cycloadditions O O of silyl enol ethers and acrylates: TTMSSO OPh TTMSSO OPh CH3 CH 3 AlCl Et O O 2 H C Ph OTBS EtAlCl2 (20 mol%) 3 + O O CH2Cl2, –78 ºC H C H3C CH3 3 Boxer, M. B.; Yamamoto, H. Org. Lett. 2008, 7, 3127–3129. Ph

• Auxiliary-Controlled Stereoselective [2+2] Cycloadditions O O TBSO TBSO • One of the earliest reports involved the use of (–)-phenylmenthol as a chiral auxiliary to achieve a OR* OR* diastereoselective [2+2] cycloaddition: + H H Ph

CH3 CH3 51%, >99% de 33%, >99% de OCH3 CH3 TsOH, PhCH3 H C Ph Cl3CCOCl OCH3 3 O H3C • O Cl 110 ºC, 70% Zn-Cu, Et O CH3 2 Cl H3C 20 ºC, >70% CH3 O O Ph 67% dr TBSO CH3 O i-Pr OTBS EtAlCl2 (20 mol%) H O i-Pr OR* OH + H C CH CH2Cl2, –78 ºC H3C 3 3 H3C CH3 Ph CH3

CH3 91%, >99% de

Takasu, K.; Nagao, S.; Ueno, M.; Ihara, M. Tetrahedron 2004, 60, 2071–2078. Greene, A. E.; Charbonnier, F. Tetrahedron Lett. 1985, 26, 5525–5528. Takasu, K.; Ueno, M.; Inanaga, K.; Ihara, M. J. Org. Chem. 2004, 69, 517–521. Fan Liu, Danica Rankic

5 Myers Cyclobutane Synthesis Chem 115

• Enantioselective [2+2] Cycloadditions with Lewis Acid Catalysts • The reaction is proposed to occur by an asynchronous process. The structures shown below were • In early reports, taddolates were found to catalyze formal [2+2] cycloadditions: presented to rationalize the stereochemical outcome:

CO2CH3 O TiCl2(Oi-Pr)2 N O H3CS SCH3 I (10 mol%) N O H3CO + H3CS 4Å MS, –78 ºC H CS O O 3 O O Ph Ph toluene 96%, 98% ee !+ petroleum ether H3C N B O H3C N B O O Ph Ph Br3Al O H Br3Al O H H3C O OH F CH CO H F CH CO H H Ph O OH 3 2 H 3 2 H I Ph Ph O

N O O O TiCl2(Oi-Pr)2 H3CO2C • (H3C)3Sn SCH3 I (10 mol%) Transformations of the cyclobutane products: H3CO O N O + C O 4Å MS, 0 ºC Sn(CH3)3 toluene SCH3 H H petroleum ether 93%, 96% ee dr > 20:1 1. CH3ONHCH3•HCl O O TBSO CH3MgBr TBSO Hayashi, Y.; Narasaka, K. Chem. Lett. 1989, 793–796. OCH CF THF, –30 ºC CH Hayashi, Y.; Niihata, S.; Narasaka, K. Chem. Lett. 1990, 2091–2094. 2 3 3 2. CH3MgBr, THF CH CH • An aluminum bromide oxazaborolidine complex was found to be a highly efficient catalyst: 3 –30 " 0 ºC, 85% 3

TBAF, THF H Ph 0 " 23 ºC O O H Ph O II (10 mol%) O OCH CF OCH2CF3 N O + 2 3 B CH2Cl2, –78 ºC Br3Al O CH3 OH H NaOH, MeOH 87%, 99% ee O CH3 dr > 99:1 II 23 ºC, 80% (2 steps) CH3 CH3

OTIPS O TIPSO O II (10 mol%) OCH CF + OCH2CF3 2 3 CH2Cl2, –78 ºC H Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686–12687. 99%, 99% ee dr = 99:1

Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686–12687. Fan Liu

6 Myers Cyclobutane Synthesis Chem 115

• Photoredox Catalysis • Cis-olefins are isomerized during the course of the reaction: • Photoredox catalysts absorb light in the visible region and provide a pathway for cyclization mediated by electron transfer rather than direct photoexcitation of the substrate:

H3CO OCH3 MeO 5 mol% Ru(bpy) (PF ) 5 mol% Ru(bpy)3(PF6)2 3 6 2 Ph 15 mol% MV(PF6)2 15 mol% MV(PF6)2 Ph Ph Ph visible light visible light H H H H H CO O MgSO , MeNO 3 MgSO4, MeNO2 4 2 O 88%, dr >10:1 71%, dr = 6:1 O O

MV2+ = methyl viologen (N,N'-dimethyl-4,4'-bypyridinium) • Limitation of the method: at least one of the styrenes must bear an electron-donating substituent at the para or ortho position. Aliphatic olefins are not suitable reaction partners. H3C N N CH3

• Mechanism: • Photoredox catalysis can also be used for [2+2] cycloadditions of enones: 2+ H3C N N CH3 (MV ) 2+ *Ru(bpy)3 visible light strong reductant Me N N Me +1 e- visible light O O Ph O O Ph (MV-radical) Ru(bpy) Cl (5 mol%) 3 2 Ph Ph Ru(bpy) 2+ Ru(bpy) 3+ product H H 3 3 LiBF4, i-Pr2NEt photocatalyst strong oxidant MeCN, 89%, dr >10:1 MV2+ +1 e– OCH3 -1 e- MV-radical

p-CH OC H O O 3 6 4 O O visible light Ph p-CH3OC6H4 Ph Ru(bpy)3Cl2 (5 mol%) H H Ph CH3 Ph CH3

OR O LiBF4, i-Pr2NEt H3C CH3 O MeCN, 84%, dr >10:1

• Upon photoexcitation, the photocatalyst (Ru(bpy)3(PF6)2) acts as a strong reductant, reducing MV by a single electron. • The resulting Ru(III) species acts as a strong oxidant, which oxidizes the electron-rich styrene to produce a radical cation and regenerates photocatalyst. Ischay, M. A.; Anzovino, M.E.; Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2008, 130, 12886–12887. • The resulting radical cation undergoes cyclization. Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2009, 131, 14604–14605.

Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572–8574. Danica Rankic

7 Myers Cyclobutane Synthesis Chem 115

• Mechanism: • An intramolecular variant was also developed. • The product can be converted to acids, esters, thioesters and amides: visible light i-Pr NEt *Ru(bpy) 2+ 2 3 CH3 N O O – visible light H3C +1 e i-Pr2NEt O O OBn Ru(bpy) Cl (2.5 mol%) N N 3 2 OBn 2+ + Li Ru(bpy)3 Ru(bpy)3 Li N H H O O LiBF4, i-Pr2NEt LiBF O 4 –1 e– MeCN, 87%, dr >10:1 Ph Ph Ph Me 1. MeOTf, CH Cl Me CH3 2 2 O O 67% O BnHN OBn 2. BnNH2, DBU CH3 H H CH2Cl2, 98% 98%, dr >10:1

Li Li O O O O O O Tyson, E. L.; Farney, E. P.; Yoon, T. P. Org. Lett. 2012, 14, 1110–1113. –1 e– Ph CH3 Ph CH3 Ph CH3 • Styrenes and alkenes undergo [2+2] cycloaddition in the presence of an Ir catalyst (III) and light. The catalyst functions as a photosensitizer. H3C H3C H3C CF F 3

• Lewis acid coordination decreases the reduction potential of the enone, facilitating single electron N t-Bu transfer. N F PF – visible light III 6 Ph CH3 Ir CH3 Ph F • Limitation of the method: one coupling partner must be an aromatic ketone. Aliphatic ketones and III (1 mol%) CH3 N esters do not under go cycloaddition because of their higher reduction potentials. CH3 H H N t-Bu DMSO, 83% O O F CF III Ischay, M. A.; Anzovino, M.E.; Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2008, 130, 12886–12887. 3 Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2009, 131, 14604–14605.

H3C CH3 OH CH3 visible light HO H H • !,"-Unsaturated 2-imidazolyl ketones also undergo photochemically induced cycloadditions: EtO2C III (1 mol%) EtO2C CH3 •

H3C O DMSO, 86% H3C O CH3 CH3 visible light H C O O H C O O 3 Ru(bpy) Cl (2.5 mol%) 3 N 3 2 N LiOH CH H3C CH3 CH3 3 HO 60 ºC N H H N LiBF4, i-Pr2NEt HO C i-Pr i-Pr 2 97% MeCN, 73%, dr >10:1 •

H3C O CH3 (±)-cannabiorcicyclolic acid

Lu, Z.; Yoon, T. P. Angew. Chem. Int. Ed. 2012, 51, 10329–10332 Danica Rankic

8 Myers Cyclobutane Synthesis Chem 115

• Other Methods for Cyclobutane Synthesis • Gold(I)-Catalyzed Ring Expansion of Cyclopropanes • Brook Rearrangement of 1,4-Dicarbonyls • Alkynyl cyclopropanols can undergo ring expansion upon treatment with catalytic Au(I):

• Treatment of keto acylsilanes with organolithium reagents produces highly functionalized cyclobutanes favoring cis-stereochemistry between newly formed alcohols

[(p-CF C H ) P]AuCl (0.5 mol%) t-Bu 3 6 4 3 AgSbF (0.5 mol%) PhLi, THF 6 O t-Bu HO TBS i-Pr TBSO OH HO OTBS CH Cl , 23 ºC, 98% O O 2 2 –80 " –30 ºC Ph i-Pr Ph i-Pr 67% 10% single isomer

Mechanism: • The mechanism is proposed to involve a stereospecific 1,2-alkyl shift:

[(p-CF C H ) P]AuCl (1 mol%) TBS i-Pr Ph i-Pr TBSO OH Ph 3 6 4 3 O O O TBS O Ph i-Pr AgSbF6 (1 mol%) O Ph Ph Li TBSO CH2Cl2, 23 ºC, 94% Brook rearrangement H3C CH3 H3C CH3

H+ Takeda, K.; Haraguchi, H.; Okamoto, Y. Org. Lett. 2003, 5, 3705–3707. Ph AuL AuL • Ring Expansion of Cyclopropanes via Pinacol-Type Rearrangements TBSO O Ph

H C CH • Hydroxycyclopropyl carbinols can be ring-expanded by treatment with protic or Lewis acids. 3 3 H3C CH3 • Either cis- or trans-substituted cyclobutanones could be produced from a single diastereomer of a an !-hydroxycyclopropyl carbinol: Markham, J. P.; Staben, S. T.; Toste, D. F. J. Am. Chem. Soc. 2005, 127, 9708–9709.

O BF3•Et2O HO p-TsOH•H2O O (20 mol%) (10 mol%) Ph n-Bu Ph n-Bu THF, 23 ºC OH CHCl3, 23 ºC Ph n-Bu

80% single diastereomer 94% 17:1 cis:trans 1:17 cis:trans

concerted thermodynamic migration proposed product

Hussain, M. M.; Li, H.; Hussain, N.; Urena, M.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 6516–6524. Danica Rankic

9 Myers Cyclobutane Synthesis Chem 115

• Cu-catalyzed 1,4-Ring closure • The products can be derivatized: • Homoallylic sulfonates can undergo borylation/cyclization using a CuI catalyst: 1. H2O2, NaOH Bn(H3C)2Si BPin THF, 0 ºC Bn(H3C)2Si OBz

H3C CH CuCl (5 mol%) 3 H3C CH3 O O 2. PhCOCl, C5H5N dppp (5 mol%) O CH3 H3C CH3 OMs B B CH2Cl2, 0 ºC Ph B CH3 H C CH Ph O 3 O O 3 1. LiCH2Cl, THF 61% (2 steps) 1. TBAF, THF H C CH B2pin2, KOt-Bu 3 3 –78 " 23 ºC 23 ºC THF, 23 ºC B2pin2 2. H O , NaOH 2 2 2. H2O2, KHCO3 THF, 0 ºC CH3OH, 23 ºC 3. PhCOCl, C5H5N H C CH2Cl2, 0 ºC 3 CH3 HO OBz CuCl (5 mol%) 73% (3 steps) O CH3 dppp (5 mol%) (H3C)2PhSi B O CH3 OMs R3Si OBz (H3C)2PhSi 49% (2 steps) B2pin2, KOt-Bu THF, 23 ºC 1. TBAF, THF 23 ºC 2. H O , KHCO • Mechanism: 2 2 3 HO OBz CH3OH, 23 ºC 57% (2 steps) R2 OMs R pinB Ot-Bu 1 (dppp)Cu Bpin (dppp)CuI-Bpin pinB!Bpin R2 H 1. BCl , CH Cl R1 3 2 2 Ph BPin 23 ºC Ph NHBn OMs CuCl (dppp)CuIOt-Bu 2. BnN3, CH2Cl2 0 ºC, 57% +KOt-Bu

R1 R2 Bpin Bpin • R2 R2 Bpin R Note that in each case the stereochemistry of the starting material is preserved in the product. R 1 1 H H I tBuO CuIII t-BuO Cu + dppp dppp K OMs KOMs

• Limitation of the method: only aryl- or silyl-substituted olefins react; alkyl olefins do not undergo borocupration.

Ito, H.; Toyoda, T.; Sawamura, M. J. Am. Chem. Soc. 2010, 132, 5990–5992. Markham, J. P.; Staben, S. T.; Toste, D. F. J. Am. Chem. Soc. 2005, 127, 9708–9709. Danica Rankic

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