Baran Lab GM S. McKerrall Singlet Oxygen in Organic Synthesis 03/19/11

Reviews: Acc. Chem. Res. 2008, 1001 Prototypical Singlet Oxygen Reactions Tetrahedron, 2006, 5308 Ene: Tetrahedron, 2005, 6665 Characteristics of Singlet Oxygen Pure Appl. Chem., 1975, 481 R1 R1 H R2 1 H R2 R1 R2 Chem. Rev., 1981, 91 O2 - 94.3 kJ/mol above Triplet State O O - Singlet Triplet transition is spin forbidden HOO - Lifetime of 74 minutes in gas phase [2+2] - Solution lifetime is highly solvent dependent R O 3 1 O O -CCl4 : 59 ms O2 R4 O R R R -Benzene : 30 s 3 1 3 R1 R -H O : 3.5 s 4 R2 R4 2 R2 R1 R2 [4+2] Generation and Reaction Conditions Concerted

-Easily generated using light and a suitable photosensitizer 1O O -Typically sensitized with Methylene Blue, 2 Tetraphenylporphryin, or Rose Bengal O O O Ph Ph N Heteroatom Oxidation N 1 Chem. Rev., 2008, 1052 O2 Me N S NMe Ph3P PPh3 OO 2 2 NH HN Methylene Blue Cl Relative Rates of Reaction Cl N Cl Ph Ph O Tetraphenylporphryin Cl 25 1 I O I 0.16 H N HO O OH O O

I I N Rose Bengal 11 233 40 - Can also be generated by decomposition of hydrogen peroxide or organic peroxides - Typical reaction conditions involve irradiation at low temperature because of the instability of many organic peroxides 43 3.1 1985 Frimer, A. A., Singlet O2,

1 Baran Lab GM S. McKerrall Singlet Oxygen in Organic Synthesis 03/19/11

RHN O '[2+2] Cycloadditions' '[2+4] Cycloadditions' cont. O O O O CDCl3 O MeO OMe 1 RHN O O Olefin + O2 NMe MeO OMe "High Yield" 94% Air, hv RHN O O O O O 67% RHN O Ph Ph OMe RHN O O O Solid O O O 100% 80% O 100% O RHN O -Most significant limitation is a lack of protons because NC the competing 'ene' reaction is significantly faster. O O '[2+4] Cycloadditions' 1 O2 O 1 O O O2 O O HN N O OOH O H N N N O 73% 2 O R > 95% O OO H N HN TPP, O2, hv HN NH O O Diene + 1O O 2 N DCM; DMS N N O O H2N N Mechanism? HN H O R R ~100% 74% JACS, 2004, 16777 O MeO O MeO OTES O O O HO OTES OMe O OMe 98% O O2, hv MeO O O O O Hunigs Base 90% OTES O O RB, DCM O H OMe -78 C 88% Handbook of Synthetic Photochemistry, 353 Tet. Let., 2008, 10831

2 Baran Lab GM S. McKerrall Singlet Oxygen in Organic Synthesis 03/19/11

Regioselectivity of the Ene Reaction Ene Reactions O "Cis Effect" O2 O H HOO 1 k1 k2 k3 O HOO MeO 1 2 O2 MeO MeO MeO HOO Mechanistic Details: 100% 72%

OMe OMe Exciplex Formation: OMe - Rate of reaction is > 103 less than diffusion control 1 O2 OMe O OOH 1 - Reactions are characterized by low (or negative) O2 O activation enthalpies and high activation entropy 100% H Periperoxide: Tet. Let. 100% - Inter vs Intramolecular Isotope Effects , 1977, 2517 Tet. Let., 1978, 3227 Ph Ph Ph Ph H3C CH3 D3C CD3 Steric and Electronic Effects H C CH D C CD H H OOH 3 3 3 3 H3C CH3 D3C CD3 1 O2

CCl4 k /k = 1.08 H D kH/kD = 1.11 H H 92:8 dr D C CH 3 3 H3C CH3 Tet. Let., 1992, 443 H C CD 3 3 D3C CD3 k /k = 1.40 H D kH/kD = 1 OMe Cl F

Cl F Ene Reaction is Suprafacial MeO Cl Cl F F H Me H DOO H Trans/Cis 79:21 80:20 48:52 46:54 D 1O Me 2 Ph JACS Ph + Ph , 1978, 6510 D H3C H HOO H In-situ ene/epoxidation OH 1 O2 Tetrahedron, 2000, 9151 O 16% Ti(OiPr)4

91% JACS, 1989, 203 98:2 cis:trans 3 Baran Lab GM S. McKerrall Singlet Oxygen in Organic Synthesis 03/19/11

Synthetic applications of [4+2] and of resulting endoperoxides O O

Me Me 1 Me 1) O2, MB, hv Me O2 O O OMe O OMe O Naturwissenschafen, 1944, 157 2) RuCl (PPh ) quant. Me H 2 3 2 Me H Me Me O O -terpene ascaridole Org. Lett., 2005, 2901 Me Me Elysiapyrone A CH OBz CH2OBz 2 CH2OBz CH2OBz O O OAc O O O 1 O2 (MeO)3P O O O O O 80% O 88% 1 KOAc OAc O2 O O rt Senepoxide O 65% O O JACS, 1978, 352 94% OH Named CH OBz CH2OBz CH2OBz 2 O CH2OBz Reaction? 1 O Org. Lett. 2009, 1591 O OH O2 OAc O OH O 15% O 56% O O O OAc O O O Crotepoxide H Tet. Lett., 1977, 3361 H O O (+)-Phomactin 1O O 2 O O O O O O OH O O O O Fusicogigantone HO 1 Fusicogigantepoxide PIFA O2 30% 20% O O Fusicocca-2(6),3-diene DCM Tet. Lett., 1994, 8205 CH3CN O OtBu 54% 95% Br Br O O Steps Br PPh3=CHCO2tBu O H2, Pd/C Ar C7H15 LiBr, 15d O 90% Ar C7H15 O 55% 8 Step synthesis OH OH O Mechanism? of Ryanodine BCE O OH H ring system N Br Ph O Org. Biomol. Chem., 2006, 323 C7H15 Tet., 2003, 8855 O Grenadamide O HO Br 4 Baran Lab GM S. McKerrall Singlet Oxygen in Organic Synthesis 03/19/11

Synthetic applications of [4+2] and of resulting endoperoxides (cont).

H OH OMe OMe OMe OMe O OMe H H O O 1 O O 1 O Al/Hg 1. O2 2 O OH H H 58% 2. H2SO4 H over H 67% HO 2 steps OMe CO2Me Chem. Eur. J., 1999, 646 O O O O 1O 2 O Al2O3 36% R OMe OMe OMe OMe OMe OMe

Solanone Soloanofuran H2SO4 O Helv. Chem. Act., 1972, 265 O

O OMe Reactions of Singlet Oxygen with Arenes OMe OH2

O2, TPP, hv O acetone O OMe OMe OMe OMe O OMe -40 C, 5d 1 56% HOO 1. O2 Mechanism? J. Org. Chem., 1998, 8544 2. H2SO4 57% OH OH O OH MeO C OMe 1:1 2 R2 1 R2 O2, NaBH4 + then Air OBn O OBn OMe O OMe R1 R1 OH OH O O OH O BnO HO CO2Bn CO2Me CO2Me O H O Me O Me OH Ar J. Org. Chem., 1998, 4403 HN N OH O H HO (-)-Balanol OH Vineomycinone B2 Methyl Ester JACS, 1991, 6320

5 Baran Lab GM S. McKerrall Singlet Oxygen in Organic Synthesis 03/19/11

Reactions of Singlet Oxygen with Furans 1 + O O2 O O H O O 1 O H O2 -HCO2Et 42% CHO OH O O O O O O O EtOH O O O JACS, 1962, 4611 Furfural OHC Chem. Abstr., 1956, 5035 1O O 1 2 O TBAF O2 O CO H O 2 OEt Ibid. 1977, 3361 MeOH EtOH OTBDPS MeO 72% O O 96% OTBDPS

O O 1 H C O2 3 OMe O MeO O OOH O MeOH O O O CH3 O O Tet., 1967, 2583 1 (+)-Decarestrictine L Tet. Lett., 2006, 1333 O O2 + OMe aq. H OH O O O TMS MeOH O O O HO O O Ann. Chem., 1953, 156 O 1) 1O H Ann. Chem., 1966, 42 2 OMOM O OMOM 1 2) NaBH4 O O2 O O O CeCl SiMe3 O O 3 MeOH O O H Me3SiO O H Me3Si Tet. Lett. 1981, 3505 1) PPTS O 2) IBX 36% brsm O O O O O O HO H H O H H OH OMOM H O , Rose Bengal H H 2 OH H hv, iPr EtN, DCM 2 H H 78% JACS, 1997, 12425 O O R R Org. Lett., 2000, 3177 Pallavicinolide Dysidiolide Angew. Chem. Int. Ed., 2009, 2351

6 Baran Lab GM S. McKerrall Singlet Oxygen in Organic Synthesis 03/19/11

Using Furan Endoperoxides in Cascade Reactions Using Furan Endoperoxides in Cascade Reactions (cont.)

R3 R2 Me3Si R1 O OH O O2, Rose Bengal O O R MeOH, 5 C O O 3 OH Ar R2 then DMS i) O , RB, hv O O R1 2 O Name Reaction? Ar MeOH, 2 min 2-97% ii) SiO2 O Ar Ar 80% R2 OH OH cis:trans 2:1 R2 SiMe3 R3 DMS O Core of Prunolides O R3 R1 E:Z = 3:1 MeO OOH Ar = p-anisyl Org. Lett. 2005, 2357 R1 O

O OH Biomimetic Synthesis of Peroxide Containing Natural Products HO 1)NaBH4 O , RB, hv 2 2) H2, Pd/C OH OH OH Et O O O MeOH, 5C; 80% TPP, O2 DTBN R2 R2 OH DMS; TsOH O O R1 R2 hv R1 65% R1 2 Steps, Enantiopure 53% Et Et 2-Hydroxy-exo- 62% OOH 1:1.2 OOH Org. Lett., 2011, 1166 brevicomin

R1 O O R MeO C16H33 HO 2 CO Me CO Me R2 1 O O 2 2 O2, MeOH; C16H33 H MeO H R R O O O 1 3 DMS; TsOH Me (+)-Plakorin (+)-Chondrillin R 3 71-90% O J. Org. Chem., 1999, 1789 H OH Org. Lett., 2009, 313 1 O2 1) AcCl, Py O 79% 2) dil. HCl O O OH 1 37% O2, MeOH 7 OOH 9:1 A:B O O Clavukerin A Clavukerin C DMS, CHCl ; O O 3 O 8 Steps (39%) O TsOH O OH 49% Me + O O O 7:3 dr at C-7 Clavulerin A Clavulerin B Chem. Comm., 2010, 259 ABC ring system of the J. Org. Chem., 1991, 6829 Pectenotoxins 7 Baran Lab GM S. McKerrall Singlet Oxygen in Organic Synthesis 03/19/11

Biomimetic Synthesis of Peroxide Containing Natural Products (cont.) O O 1) TIPSOTf O HO O O TEA O O O 2) s-BuLi OH O Geranyl-Br OMe 51% 1) nBuLi, TMSCl H DIBAL-H 85% O 2) O2, MB, hv 1 O O2, hv 2 min + MeOH 30s OOH H 97% H H Coronarin E DMS; Sesquirosefuran Chinensine B Chinensine A Hunigs Base 20% 60% 52% 1) NaBH4 OH 2) DIBAL-H OH O 1 88% H O2, 2 min H O OH OH O

CHO OHC OH O O O O Litseaverticillol A +3% Litseaverticillol C (cis) O O O2, MB, hv H H 20 min OH + OH 60% OH OOH H H 1.3:1 D:E H H

H H H O PPh3 O Chinensine E Chinensine D Chinensine C Litseaverticillol D OH J. Org. Chem., 2007, 4826 OH + 70% + 2:1:1 O H O H D:F:G

O O OOH TMS O O OH O O Litseaverticillols F, G O 1 O OH O2 2.5 min O + OH OH OH then SiO2 H H H 73% OH H H H Premnalane A O O Litseaverticillols I, J O Litseaverticillol B Litseaverticillol E 1.2:1 - 4:1 (revised) (not known) Org. Lett. 2007, 5585 Angew. Chem. Int. Ed., 2003, 5465 Chem Eur. J., 2005, 5899

8 Baran Lab GM S. McKerrall Singlet Oxygen in Organic Synthesis 03/19/11

Cl Reactions of other heterocycles with Singlet Oxygen 2 Cl2 Nuc: heterocycles, Sn Sn Enol ethers, etc O O O O HO SnCl2 Nuc O O NMe NMe 1O NMe N 35-70% N Nuc 2 H N N R R R R 37% H 1979 O O Tet. Lett., , 3473 Mechanism? O O Misc. Singlet Oxygen Chemistry O MeO Alpinine JACS, 1974, 1944 1 O2 Ph Ph Chiral Zeolite OOH 15% e.e. 1 Tet. Lett., 1997, 8825 O2 O O O TsOH H 88% O Schenck at his ascaridol pilot plant in 1952 O N N N Solar Photochemistry: Angew. Chem. Int. Ed., 1994, 2009 Me Me OH Me 2 O Tet. Lett., 2009, 3283 O 5 mol % OOH CO2Me O 1O N 2 CO Me NHBoc HO 2 CO2Me 1 HO HO n n O2; DMS NBoc mCPBA HO 97% yield n=1-3 N 58% NBoc 99% ee CH3CN 36-53% Me N H OAc Me H N Capsular Cl 1:1 dr O 90-95% Cl Cl N Complex Me JACS, 2005, 12556 JACS, 2007, 4132

J. Org. Chem., 2004, 7875 Other Applications of Singlet Oxygen Not Covered

OH NMe2 Me H H N O OH OMe O HO MeO2C HO HO OH O NH2 MeO CO2Me NH OH N AcO O OH O O O Me Cl MeN O H Tetracycline CJ-12662 Isochrysohermidin Classics III Classics II

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