The [3+2] Cycloaddition Reaction Lecture Notes OTBS OPMB O

Key Reviews: O Me O Me XX

Asymmetric K. V. Gothelf, K. A. Jorgensen, Chem. Rev. 1998, 98, 863.

Nitrones P. N. Confalone, Org. React. 1988, 36, 1.

Azomethine Ylides I. Coldhaim, R. Hufton, Chem. Rev. 2005, 105, 2765. [3+2] Dipolar Cycloadditions: A Reaction You Have Seen Before

B Dipolar A C cycloaddition B A C or E D E D [3+2] reaction

Criegee zwitterion O O O O O O O R1 O + Dipolar Dipolar O R2 cycloaddition R1 R2 cycloreversion R1 R2

Me2S R O O O or PPh3 1 O + in situ O R1 R2 reduction R2 [3+2] Dipolar Cycloadditions: General Reaction and Classes of 1,3-Dipoles

B Dipolar A C cycloaddition B A C or E D E D [3+2] reaction

R1 R2 N R R N O O N N N R3 nitrile oxides nitrones azides

R 1 Y N X R R1 O R4 N N R2 R2 R3 azomethine ylides diazoalkanes carbonyl ylides

X = electron withdrawing group Y = electron donating group [3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity

Regioselectivity

EWG EWG N + = N EWG O O

EWG = CO2Et, NO2

EDG EDG N + = N O O EDG = OMe, alkyl, Ph EDG [3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity

Regioselectivity Note: EWG EWG azides do not follow N + = N EWG this trend O O

EWG = CO2Et, NO2 Reactivity: EDG EDG R R + = 1 1 N N > O O R2 R2 EDG = OMe, alkyl, Ph EDG [3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity

Regioselectivity Note: EWG EWG azides do not follow N + = N EWG this trend O O

EWG = CO2Et, NO2 Reactivity: EDG EDG R R + = 1 1 N N > O O R2 R2 EDG = OMe, alkyl, Ph EDG

Diastereoselectivity

R2O R O O 1 R2O R O N R1 O 1 R1 O N N O N + OR O O OR2 N OR R1 2 O endo exo O transition state transition state Nitrile Oxides: Synthesis

H H HONH2•HCl OH R O R N R NO2

X = Cl, Br, I NaOX R N C O

-[HX] X R N O OH R N O R N nitrile oxide nitrile oxide

The isocyanate is serving as a dehydrating reagent; can you rationalize a mechanism? Nitrile Oxides: Synthesis

H H HONH2•HCl OH R O R N R NO2

X = Cl, Br, I NaOX R N C O

-[HX] X R N O OH R N O R N nitrile oxide nitrile oxide

The isocyanate is serving as a dehydrating reagent; can you rationalize a mechanism? Nitrile Oxides: Applications in Total Synthesis

O OH N N Nitrile oxide N O 1,3-dipolar Me Me aq. NaOCl, cycloaddition Me CH2Cl2, 25 °C (59%) H H OTBDPS OTBDPS OTBDPS

Zn, AcOH, (66%) OH 25 °C, 4 h N Me OTES O Me H OTMS N N H H Me MeO2C Me OH MeO OAc N MeO2C H OH OTBDPS OTBDPS Me CO2Me vinblastine T. Fukuyama and co-workers, J. Am. Chem. Soc. 1999, 121, 3791 For a review, see Classics in Total Synthesis II, Chapter 18 Nitrile Oxides: Applications in Total Synthesis

MeO C NO MeO2C O 2 2 PhNCO N A Benzene, 25 °C Nitrile oxide Me Me Me Me 1,3-dipolar (89%) cycloaddition

A O O O MeO2C N O Me O Me Me Me Me Me Me O Me O O O N A N MeO2C N O MeO C 2 N O Nitrile oxide Me 1,3-dipolar Me Me Me cycloaddition Me Me Me Me

R.V. Stevens, J. Am. Chem. Soc. 1975, 97, 5940. Nitrile Oxides: Applications in Total Synthesis

Me Me O Me Me O N O O O N N MeO2C N O MeO2C N O Me Me Me Me Me Me Me Me B O Nitrile oxide Me B 1,3-dipolar Me Me cycloaddition Me Me Me Me Me Me Me Me O N N O Me N O N Me N N MeO2C N O Me Me Me Me Me octamethylcorphin Me Me R.V. Stevens, J. Am. Chem. Soc. 1975, 97, 5940. Nitrile Oxides: Applications in Total Synthesis

Me Me Me Me Me Me Me Me O O O Me N H , Raney Ni O Me H2N O 2 O MeOH, pH 7 N H2N MeO C 2 N O MeO2C NH2 O Me Me Me Me Me Me Me Me

Et N, CHCl , 3 3 Imine formation 25 °C, 24 h Me Me Me Me Me Me Me N N Me O N COMe O N Me N NH N Me Me Me Me Me Me octamethylcorphin Me R.V. Stevens, J. Am. Chem. Soc. 1975, 97, 5940. Nitrile Oxides: Applications in Total Synthesis

NO2 -[HOAc] NO2 O2N + + OAc NaS Michael S HS addition

PhNCO

O HO H O H N O HN NH H N 2 LiAlH N H 4 H Intramolecular S S S H H H nitrile oxide S HO2C 1,3-dipolar cycloaddition biotin

P. N. Confalone, J. Am. Chem. Soc. 1980, 102, 1954. Nitrile Oxides: Applications in Total Synthesis

Me O Me O N N Cl N C O

Et3N, toluene, 80 °C NO N 2 O

Intramolecular nitrile oxide (82%) 1,3-dipolar cycloaddition

Me O N For reviews: A. Padwa, Angew. Chem. Int. Ed. Engl. 1976, 15, 123 O W. Oppolzer, Angew. Chem. Int. Ed. Engl. 1977, 16, 10. N 19-membered ring [masked aldol product]

P. N. Confalone, J. Heterocyclic Chem. 1990, 31. Nitrones: Preparative Methods

R R HgO 1 N 2 R1 N R2 + Oxime R1 NH O R OH O 2 oxidation OH nitrone Nitrones: Applications in Total Synthesis

CO2Me CO2Me H N + Nitrone N O O OH OH 1,3-dipolar cycloaddition 48 kcal

J. Tufariello, Acc. Chem. Res. 1979, 12, 396. Nitrones: Applications in Total Synthesis

CO2Me CO2Me H N + Nitrone N O O OH OH 1,3-dipolar cycloaddition 48 kcal

1. MsCl 2. H2, heat

OH H 1. cyclize H CO2Me 2. dehydrate OH N 3. LiAlH4 NH supinidine OMs

J. Tufariello, Acc. Chem. Res. 1979, 12, 396. Nitrones: Applications in Total Synthesis

CO2Me CO2Me N CO Me mCPBA 2 N N O Nitrone O O H 1,3-dipolar H O cycloaddition O O

N Oxidative DBU = N Cl ring opening

CO2Me CO2Me CO2Me N 1. MsCl, py N OH CO2Me N OH O O O 2. DBU Nitrone MeO2C MeO2C 1,3-dipolar cycloaddition [protection step]

J. Tufariello, Acc. Chem. Res. 1979, 12, 396. Nitrones: Applications in Total Synthesis

CO2Me O N CO Me xylene, Δ 2 N CO2Me O N [3+2] cycloreversion O MeO2C

Nitrone [3+2] (66% overall) cycloaddition

CO2Me Me 1. MeI N O CO2Me O Ph 2. H2 N O 3. BzCl H cocaine

J. Tufariello, J. Am. Chem. Soc. 1978, 100, 3638. J. Tufariello, J. Am. Chem. Soc. 1979, 101, 2435. Nitrones: Applications in Total Synthesis

O O OH OH N HN H H H H NOH•HCl + SnCl4 2 NaBH3CN Me (67%) Me (98% Me overall) Me Diels-Alder H H H reaction

H O H

O Me Me H H H MeO S F H N N N N CrO O Me O Me 3 Me O Me H H H HO H LiAlH Nitrone 4 [3+2] (94% O H cycloaddition H H H overall) luciduline

W. Oppolzer, M. Petrzilka, J. Am. Chem. Soc. 1976, 98, 6722. W. Oppolzer, M. Petrzilka, Helv. Chim. Acta 1978, 61. Nitrones: Applications in Total Synthesis

Me CO2Me Me N Me Me O MeO C Me Me Me 2 Me Me Me Me Me 3 steps N O Me Me N O xylene, 140 °C Me Me H Nitrone HO [3+2] H HO H cycloaddition endo product HO MeI, toluene, Me 60 °C; Zn dust, Me Me AcOH Me Me OH Me Me Me Me Me H Me MeI; Me Me Me t-BuOK Me HO N HO Hofmann Me Me degradation H H HO OH HO HO 1α,25-dihydroxyergocalciferol E. G. Baggiolini and co-workers, J. Org. Chem. 1986, 51, 3098. Nitrones: Applications in Total Synthesis

CN 1. A, O MgBr O CN O EtO H 2. PCC, CH2Cl2 Olefin cross- (91% overall) metathesis (62%) Me Me Me Me CN N N Cl Me Me Intramolecular Ru H NOH•HCl, NaOAc, Cl 2 nitrone [3+2] O MeOH/MeCN, 50 °C A i-Pr cycloaddition

CN CN CN

O HO HO N N N 1,3-proton Michael shift addition

CN CN CN

P. L. Fuchs and co-workers, J. Am. Chem. Soc. 2006, 128, ASAP. D. L. Hughes and co-workers, J. Org. Chem. 2004, 69, 1598. Nitrones: Applications in Total Synthesis

CN CN Intramolecular CN O nitrone [3+2] N O cycloaddition N O N (89% overall) NC NC H CN kinetic product

toluene, 180 °C Retro [3+2] For original concept, see: sealed tube cycloaddition R. Grigg, J. Chem. Soc., Perkin Trans. 1 1984, 47

CN CN Intramolecular O N nitrone [3+2] N HN O cycloaddition HO (95%) CN thermodynamic CN histrionicotoxin product

P. L. Fuchs and co-workers, J. Am. Chem. Soc. 2006, 128, ASAP. D. L. Hughes and co-workers, J. Org. Chem. 2004, 69, 1598. Carbonyl Ylides (Oxidopyryliums): Using Cyclic Systems

O O O Base -[ OAc]

AcO O AcO O O

O H 1,3-Dipolar O 1 2 O O cycloaddition R R R1 O H O 2 R R1 R2 exo adduct

In cyclizations of this type, the ENDO isomer places the substituents on the dipolarophile anti to the oxido bridge. Accordingly, the EXO isomer is the one in which these substituents are syn to the resultant oxygen bridge. Carbonyl Ylides (Oxidopyryliums): Using Cyclic Systems

11 OAc O O TBSO OAc 8 DBU, Me 11 CH2Cl2, 25 °C 8 O O AcO H Oxidopyrylium Me formation OTBS

1,3-Dipolar (92%) cycloaddition HO OH Me AcO OAc Me Me H O Me H H Me H OH O Me OH O O OH OTBS O OTBS phorbol exo adduct

P.A. Wender and co-workers, J. Am. Chem. Soc. 1989, 111, 8954 and 8957. Carbonyl Ylides (Oxidopyryliums): Using Cyclic Systems

OBn OBn Me Me O DBU, Me OAc O OAc CH CN, O OAc O 3 O O OBn OAc 80 °C, 1 h OTBS OTBS OTBS

1,3-Dipolar (84%) cycloaddition Me OAc O O Me Me Me OBn OAc H O H H OBn O O O O Me O OMe OTBS OTBS OH O O exo adduct OH resiniferitoxin

P.A. Wender and co-workers, J. Am. Chem. Soc. 1997, 119, 12976. For a review, see: Classics in Total Synthesis II, Chapter 6 Carbonyl Ylides (Oxidopyryliums): How to Make Precursors

OBn OBn OBn Me mCPBA, Me Me OTBS THF, OTBS -[H ] OTBS O OAc O OAc O OAc OH 0→25 °C, OH OH 12 h O OH

OBn OBn Note: Although the free hydroxyl Me Me controls the addition of oxygen to the indicated bond of the furan, O OAc Ketalization O OAc O OH had addition to the other olefin OH occurred, the same butenolide (100%) O product would have resulted OTBS (i.e. degenerate OTBS mechanistic pathways)

P.A. Wender and co-workers, J. Am. Chem. Soc. 1997, 119, 12976. For a review, see: Classics in Total Synthesis II, Chapter 6 Carbonyl Ylides (Oxidopyryliums): Applications in Total Synthesis

1. O NH NH2 N N MeO HN O MeO 2. O N HN O N H2N Me Me N CO2Me CO Me H 2 AcOH, THF (74% overall) Robinson- TsCl, Gabriel Et3N Cyclo- dehydration Et O OBn N O NH Et N OH N MeO O MeO O N N EDC, 4-DMAP N N BnO Me (78% overall) CO2Me Me CO2Me

D.L. Boger and co-workers, J. Am. Chem. Soc. 2006, 128, 10597. D.L. Boger and co-workers, J. Am. Chem. Soc. 2006, 128, 10589. Carbonyl Ylides (Oxidopyryliums): Applications in Total Synthesis

O O TIPB, N N 230 °C [-N2] Et Retro N MeO N MeO O Hetero O Et Diels-Alder N N Diels-Alder N N reaction BnO reaction OBn Me Me CO2Me CO2Me O

Concurrently forms: N 4 C-C bonds 6 stereocenters (4 quaternary) MeO O 3 rings Et N OBn O Me CO2Me N H N Et [3+2] Et cycloaddition MeO OAc O N MeO OBn H OH (53% overall) Me CO2Me N H CO Me (−)-vindoline Me 2

D.L. Boger and co-workers, J. Am. Chem. Soc. 2006, 128, 10597. D.L. Boger and co-workers, J. Am. Chem. Soc. 2006, 128, 10589. Azomethine Ylides: Formation

R R1 O + HN R2

R R R N Base R1 N R2 R1 N R2 R1 R2 Electrocyclic ring-opening azomethine ylide

-[H2O]

O CO2H

R1 N R2 R

For a review, see: I. Coldham, R. Hufton, Chem. Rev. 2005, 105, 2765. Azomethine Ylides: Huisgen's Pyrrole Synthesis

O O CO2H O -[H2O] N N

[3+2] cycloaddition

O

O -[CO2] N Retro N Diels-Alder reaction Azomethine Ylides: Applications in Total Synthesis

O Me O MeO2C MeO2C O O MeO2C O CO2H Ac2O O Δ O -[H O] Me N Me N 2 Me N

Retro MeO2C CO2Me Diels-Alder [3+2] reaction cycloaddition -[CO2]

OCONH O 2 O MeO C MeO 2 CO Me MeO2C CO2Me OMe 2 KH, THF MeO2C Me Dieckmann Me N NH N cyclization Me N O mitomycin A

J. Rebek, Tetrahedron Lett. 1977, 3027. Azomethine Ylides: Applications in Total Synthesis

O O O hν, HO HO N HO MeN3 Pyrex MeO N MeO N N MeO N N Me toluene, N dioxane 25 °C Me (90%) O [3+2] addition MeO Me MeO (99%)

A Me Me O hν, Electrocyclic N quartz ring-opening O2S

Me N Me H N O HO O O Me CO2H HO N N N CONX A H MeO N MeO O [3+2] MeO Me addition Me O

quinocarcin exo product

P. Garner, W.B. Ho, H. Shin, J. Am. Chem. Soc. 1993, 115, 10742. Azides: Regioselectivity and Reactivity

N N N R N N N R N R2 N 2 2 N N R2 N N Δ + (~1:1) [3+2] R 1 cycloaddition R1 R1

K. B. Sharpless and co-workers, Angew. Chem. Int. Ed. 2002, 41, 2596. K. B. Sharpless and co-workers, J. Am. Chem. Soc. 2005, 127, 210. Azides: Regioselectivity and Reactivity

N N N R N N N R N R2 N 2 2 N N R2 N N Δ + (~1:1) [3+2] R 1 cycloaddition R1 R1

CuX R1 R CuL rt, 12-24 h 1 As you might expect, this selectivity can only N N N R2 occur with alkynes bearing a terminal hydrogen

N R N N 2 R1 CuL N N R2 R1 N only product formed

K. B. Sharpless and co-workers, Angew. Chem. Int. Ed. 2002, 41, 2596. K. B. Sharpless and co-workers, J. Am. Chem. Soc. 2005, 127, 210. Azides: Applications in Total Synthesis

OBn OBn O O OBn CuI, DBU; BnO OBn H2, Pd/C O O OBn OH BnO OBn (80%) OH O O Tandem O OH BnO [3+2] O HO HOO N cycloaddition HO O OH HO O OH N N OH O N N N O O HO OH HO HO O N N OH N HO O HO OH HO OH O α-cyclodextrin O OH O HO HO O OH OH OH O O O OH HO HO O O OH OH OH HO OH O O HO O HO K.D. Bodine, D.Y. Gin, M.S. Gin, J. Am. Chem. Soc. 2004, 126, 1638. Azides: Applications in Total Synthesis

Ph Ph toluene, OBn OTMS 110 °C, OBn OTMS SEt SEt MeO O 3 h MeO O O (86%) H O Me N [3+2] Me N H N cyclo- OMe N OMe N N addition

T. Fukuyama, L. Yang, J. Am. Chem. Soc. 1989, 111, 8303. Azides: Applications in Total Synthesis

Ph Ph Ph toluene, OBn OTMS 110 °C, OBn OTMS OBn OTMS SEt SEt SEt MeO O 3 h MeO O MeO O O (86%) H O H O Me N [3+2] Me N H Me N H N cyclo- OMe N OMe N N N addition OMe N

T. Fukuyama, L. Yang, J. Am. Chem. Soc. 1989, 111, 8303. Azides: Applications in Total Synthesis

Ph Ph Ph toluene, OBn OTMS 110 °C, OBn OTMS OBn OTMS SEt SEt SEt MeO O 3 h MeO O MeO O O (86%) H O H O Me N [3+2] Me N H Me N H N cyclo- OMe N OMe N N N addition OMe N

[-N2]

Ph O OCONH2 OCONH2 NH , O OBn OTMS 3 OMe SEt H2N OMe MeOH MeO NH MeO O (85%) H H O Me N NH Can you Me N Me N rationalize O O OMe a mechanism? mitomycin C isomitomycin A

T. Fukuyama, L. Yang, J. Am. Chem. Soc. 1989, 111, 8303.