- Overview and Recent Advancements -

Jan Streuff

Stoltzgroup - Literature Seminar 01-26-2009, 8pm 147 Noyes Some Properties of

Physical Properties:

H N possibly carcinogenic absorbed through skin bp = 57°C pKa (of conjug. acid) = 7.98 potential : interacts with DNA nucleobases

Strain energy:

H N O S

experimental : 26.7 kcal/mol 27.5 kcal/mol 26.3 kcal/mol - (calculated) : (26.2 kcal/mol) (27.3 kcal/mol) (24.6 kcal/mol) (18.9 kcal/mol)

J. B. Sweeney, Chem. Soc. Rev. 2002, 31, 247. R. D. Bach, O. Dmitrenko, J. Org. Chem. 2002, 67, 3884. Inversion Barrier

H N N H H H OMe ΔG = 16.7 kcal/mol O N (inversion at 25°C) Cl O NH Cl Me N N Cl no inversion at 50°C H H ΔG = 26.8 kcal/mol (diastereomers isolable at 25°C)

J. B. Sweeney, Chem. Soc. Rev. 2002, 31, 247. DNA Interaction of Aziridines

O O NH2 O 1 2 1 2 R OR O R OR

3 N N R N N CH3 O O

1 2 3 1 2 Mitomycin A R = OMe, R = Me, R = H Mitomycin G R = NH2, R = Me Mitomycin B R1 = OMe, R2 = H, R3= Me Mitomycin H R1 = OMe, R2 = H 1 2 3 1 2 R = NH2, R = Me, R = H Mitomycin K R = OMe, R = Me 1 2 3 Porfiromycin R = NH2, R = Me, R = Me

OC(O)NH2 1 2 3 4 OR2 FR-900482 R = CHO, R = R = R = H FR-66979 R1 = CH OH, R2 = R3 = R4 = H OR3 2 FR-70496 R1 = CHO, R2 = Me, R3 = H, R4 = Ac 1 2 3 4 O N R4 FK-973 R = CHO, R = R = R = Ac R1 N FK-317 R1 = CHO, R2 = Me, R3 = Ac O

J. B. Sweeney, Chem. Soc. Rev. 2002, 31, 247. DNA Interaction of Aziridines

O O NH2 1 2 R OR O

N N R3 O O NH P O 2 O O + 2e , + 2H OH O 2 − HOR 1 R H N N OH O NH2 N O O 1 N R H HN O N OR NH N N R3 R3 O OR DNA

H O NH HO O NH2 O 2 1 R1 R O O H DNA N N R3 N OR N R3 OR H J. B. Sweeney, Chem. Soc. Rev. 2002, 31, 247. Other Natural Products Containing Aziridines

O O OH O NH H H Miraziridine N N HO N N N NH2 H H H N O O H

CO2H O O O H MeO N O N CO2H H H H2N O O Azinomycin A O N Ficellomycin O N HN O HO NH H OH HO H2N O N OMe R H HO N OH H HO O O O N Cl MeO H O OH H O OH OH O OH OH Azicemicin A: R = H Azicemicin B: R = Me Maduropeptin MeO Classic Aziridine Syntheses

Wenker's Synthesis (1935):

H NH 2 H SO NH3 1) NaOH, 2 4 Δ N O O HO 250°C S 2) KOH 3) Na, Δ − H2O O2 610 g 71% 27%

H. Wenker, J. Am. Chem. Soc. 1935, 57, 2328.

Hoch-Campbell Synthesis (1934):

OH OMgBr BrMg OMgBr H N PhMgBr N PhMgBr N H O 2 N H Ph − C H Ph Ph − 2 MgBrOH 6 6 Ph Ph Ph

J. Hoch, Compt. Rend. 1934, 198, 1865 K. N. Campbell, B. K. Campbell, J. F. McKenna, E. P. Chaput, J.Org. Chem. 1943, 8, 103. Aziridine Synthesis - Overview

N R2 N R2 X N R2 X X MLn R1 R1 Br R1 Y

X R1 PhI=NX H NX R2 N 2 2 1 R R Ti(IV) Br R1 R2

R PX H2NX 4

SOCl2, SOCl2, [O] RSO Cl R1 2 R1 OH MN3 NaOH NHX HO PPh3 HO R2 R2 O NHX

1 R1 R2 R O

I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39, 194. T. Ibuka, Chem. Soc. Rev. 1998, 27, 145. A Brief Introduction to

Triplet : X N Singlet nitrene: X N

Energy Energy LUMO p LUMO

sp2 HOMO

sp HOMO

non bonding non bonding

slightly higher energy stabilized by electrondonating

Common nitrene precursors:

hν Oxidant R N R N X X SO2R 3 H N R N R or Δ 2 PhI X = CO, SO2 N −N2

W. Schoeller, A. B. Rozhenko, Eur. J. Org. Chem. 2001, 845. W. Lwowski in Nitrenes (Ed.: W. Lwowski), Interscience, New York, 1970, pp. 1-11. Selected Examples for the Synthesis of Aziridines from

X X N N X N

R1 H R1 H R1 H H R2 H R2 H R2

X N X N X X R1 N R1 N R2 R2 R1 R2 R1 R2 Singlet Nitrene Triplet Nitrene (stereoselective) (not stereoselective)

J. B. Sweeney, Chem. Soc. Rev. 2002, 31, 247. Copper Catalyzed Aziridinations Me Me O O

N N Ts Ph (6 mol%) Ph Ph N R = Me 63% i.y., 94% ee CO2R CuOTf (5 mol%) R = Ph 64% i.y., 97%ee PhI=NTs (2.0 equiv) Ph CO2R C6H6, 21°C D. A. Evans, M. M. Faul, M. T. Bilodeau, B. A. Anderson, D. M. Barnes, J. Am. Chem. Soc. 1993, 115, 5328. D. A. Evans, M. M. Faul, M. T. Bilodeau, J. Am. Chem. Soc. 1994, 116, 2742.

Cl N N Cl O O Cl Cl (11 mol%) 75% i.y., >98% ee CuOTf (10 mol%) NC NC PhI=NTs (1.5 equiv) N CH2Cl2, -78°C Ts Z. Li, K. R. Conser, E. N. Jacobsen, J. Am. Chem. Soc. 1993, 115, 5326. Z. Li, R. W. Quan, E. N. Jacobsen, J. Am. Chem. Soc. 1995, 117, 5889.

Via copper nitrene species: Drawbacks: Limited substrate scope L*Cu NTs OTf Often an excess of the required Copper Catalyzed Aziridination - Catalytic Cycle

L*Cu PF6

R2 3 R1 R

N PhI NTs Ts

PhI R1 R3

R2

L*Cu NTs

PF6

Z. Li, R. W. Quan, E. N. Jacobsen, J. Am. Chem. Soc. 1995, 117, 5889. Aziridinations with Ruthenium and Rhodium SES Catalyst: Catalyst (1 mol%) N Ph N3 Ph (1.0 equiv) TMS (1.0 equiv) N CO N 99% i.y., 92%ee 0°C, 12h Ru O O Ns Ar Ar N Ph Catalyst (0.1 mol%)

(1.0 equiv) NsN3 (1.0 equiv) Ph room temp., 36h 70% i.y., 81% ee Ar = 3,5-Cl2-4-(CH3)3SiC6H2

H. Kawabata, K. Omura, T. Katsuki, Tetrahedron Lett. 2006, 47, 1571.

Catalyst: Ns Catalyst (2 mol%) N Ph O R PhI=NNs (1.0 equiv) Ph O CH Cl , room temp. R P 2 2 O (20 equiv.) 1.0 − 1.5 h O Rh2 R = H: 74% i.y., 55% ee 4 R = Me: 80% i.y., 73% ee

P. Müller, C. Baud, Y. Jacquier, Can. J. Chem. 1998, 76, 738. M. C. Pirrung, J. Zhang, Tetrahedron Lett. 1992, 33, 5987. P. Müller, C. Fruit, Chem. Rev. 2003, 103, 2905. Iron Catalyzed Aziridination

Fe(OTf)2 (2.5 mol%) Ts OTMS PhI=NTs (1.0 equiv) O N H R2 N 1 1 R MS 4Å, CH CN R Ts 3 TMSO R2 room temp., 1h 1 2 (2 equiv) R R 46-72% i.y. R1 = aryl, alkyl R2 = H, alkyl

Ts Fe(OTf)2 (5 mol%) : Ligand (30 mol%) N PhI=NTs (1.0 equiv) O O N N N MS 4Å ,CH3CN room temp., 1h (20 equiv) 72% i.y., 40% ee

M. Nakanishi, A.-F. Salit, C. Bolm, Adv. Synth. Catal. 2008, 350, 1835. Main Group Element Catalyzed Aziridination Ts R2 N PTAB: R1 N PTAB (10 mol%) 1 2 Ph Chloramine-T (1.1 equiv) R R or or CH3CN, 25°C Br 12h Ts Br Br 1 R (30-95% i.y.) N Phenyltrimethylammonium R2 tribromide R1 R2 1 2 R , R = H, alkyl, aryl, CH2OH

Ts Ts N N N Ts N Ts OH 93% 51% 76% 94% Ts Ts Ts Ts N N N N OH HO Ph 8 68% 54% 73% 30%

J. U. Jeong, B. Tao, I. Sagasser, H. Henniges, K. B. Sharpless, J. Am. Chem. Soc. 1998, 120, 6844. J. U. Jeong, K. B. Sharpless, U.S. Patent number 5,929,252, 1999. Main Group Element Catalyzed Aziridination

Ph Me

"Br ": Br-X (X = Cl, TsNCl, Br, etc...) Br

"Br " Ph Me

H Br Ph H N Me Ts N Ts Cl H Br Ph H H H Ph Me + Br Me Cl N N Ts Ts

J. U. Jeong, B. Tao, I. Sagasser, H. Henniges, K. B. Sharpless, J. Am. Chem. Soc. 1998, 120, 6844. Main Group Element Catalyzed Aziridination

Ts PTAB (10 mol%) OH Chloramine-T (1.1 equiv) N (63%) OH

Ts PTAB (10 mol%) OH Chloramine-T (1.1 equiv) N OH (E/Z mix) (64%)

J. U. Jeong, B. Tao, I. Sagasser, H. Henniges, K. B. Sharpless, J. Am. Chem. Soc. 1998, 120, 6844. J. U. Jeong, K. B. Sharpless, U.S. Patent number 5,929,252, 1999.

OAc Chloramine-T (2.3 equiv) OAc OAc I2 (15 mol%) O O AcO O AcO AcO AcO AcO NHTs AcO CH3CN, 0°C 14h N NHTs Ts 69%

V. Kumar, N. G. Ramesh, Chem. Commun. 2006, 4952. Aziridination with Hydrazines With Pb(OAc)4 as oxidant: O Phth Phth Pb(OAc) N N highly diastereoselective 4 + (singlet state nitrene) N NH + 2 R -20°C R R H H

O 100 : 0 (R = Ph, CO2Me) R. S. Atkinson, M. J. Grimshire, B. J. Kelly, Tetrahedron 1989, 45, 2875. R. S. Atkinson, D. W. Jones, B. J. Kelly, J. Chem. Soc., Perkin Trans. 1 1991, 1344.

Electrochemically (platinum electrodes): O Phth + 1.8V (vs. Ag) N + R1 HNEt3OAc N NH2 2 R room temperature R1 R2 O (R1, R2 = alkyl, aryl, allyl, EWG) T. Siu, A. K. Yudin, J. Am. Chem. Soc. 2002, 124, 530.

With PhI(OAc)2 as oxidant: O Phth PhI(OAc)2 (2.0 equiv) N NH + R1 N 2 R2 room temperature R1 R2 O (R1, R2 = alkyl, aryl, allyl, EWG) L. B. Krasnova, R. M. Hili, O. V. Chernoloz, A. K. Yudin, ARKIVOC 2005, 4, 26. Aziridination with Hydrazines

Pb(OAc)4 PhI(OAc)2

O O or O O − PhI O O − HOAc O O N +1.8 V (vs Ag) N N N HNEt3OAc NH2 NH Ph NH NH2 O I OAc Problematic substrates: O Aziridinating reagent n R1 2 MeO2C CO2Me R O O H O MeO O N O O O N O N O N Br O R1 R2 R1 R2

Observed sidereaction (electrochemically and with Pb(OAc)4): O H [O] PhthN N [O] PhthN N [O] 2 PhthN NH 2 NH 2 N NPhth N NPhth N H − 2 L. Hoesch, A. S. Dreiding, Chimia, 1969, 23, 405. O I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39, 194. Aziridine Transformations - Ring Opening

R1 SR4 R1 OR4 β-Aminoalcohols β-Aminosulfides R2 NHR3 R2 NHR3 COR4 R1 NHR4 R1 COR4 Diamines R2 NHR3 R2 NHR3

N R

1 3 R NHR 1 4 27 kcal / mol R CH2R R2 2 R N R2 NHR3

R1 O 1 3 R R 1 Dimerization products R P(OR)2 N N Aminophosphonates 2 3 R3 R2 R NHR Polymers

I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39, 194. T. Ibuka, Chem. Soc. Rev. 1998, 27, 145. Concepts for the Activation of Aziridines

Activation by protonation: H H H Nuc Nuc NH2 N + Nuc H N N (basic) Nuc

H Activation by : H N CO Et 1) 2 Cl CO2Et N 2) LDA

CO2Et

N CO2Et N Cl

Isolable aziridinium compounds:

Ph3P Ph Ph Ph O CBr4

N OH PPh N Br 3 N − O PPh3 tBuO2C tBuO2C CO2tBu tBuO2C CO2tBu CO2tBu H. A. Song, M. Dadwal, Y. Lee, E. Mick, H.-S. Chong, Angew. Chem. Int. Ed. 2009, early view. Concepts for the Activation of Aziridines Activation with substituents: 1 1 1 O R1 R O OR OR S P O R1 O R1 O O N N N O 1 1 1 O R R R N N R S R P R O N N R R weak amide resonance R R (increased ) Activation with Lewis acids: R1 LA R1 LA R1 LA O X LA O X O N N N

R R R R (R1 = H, alkyl) (indirect interaction)

Kinetic activation: Thermodynamic activation:

R1 R1 O O O O Nuc N N R N R N R1 R1 R R Nuc Nuc (polarization) (stabilization) Enantioselective Opening of Aziridines

Li nBuLi (3.0 equiv) O O N SO2-t-Bu (−)-Sparteine (3.0 equiv) Li HO SO -t-Bu N 2 Et2O N -78°C to 0°C SO -t-Bu H 2 30% i.y., 25% ee D. M. Hodgson, B. Stefane, T. J. Miles, J. Witherington, Chem. Commun. 2004, 2234.

O2N NO2 Ar H Catalyst (10 mol%) N N3 Catalyst: TMSN3 (1.05 equiv) Ph MS 4Å, acetone Me N N O Ph -30°C, 48h Cr 95% i.y., 94% ee N O 3

Z. Li, M. Fernández, E. N. Jacobsen, Org. Lett. 1999, 1, 1611. Catalyst: Ph Catalyst (30 mol%) N NHTs O MeMgBr (10 equiv) Cu O N Ts O THF, 0°C O O Cu 1.5 h Me O N 52% i.y., 91% ee Ph P. Müller, P. Nury, Org. Lett. 1999, 1, 439. Catalytic Enantioselective Opening of Aziridines

i i Gd(O Pr)3 (10 mol%) Y(O Pr)3 (2 mol%) H Ligand (20 mol%) A (4 mol%) H N TFA (5 mol%) N R TMSN3 (1.5 equiv) R N R 2,6-Dimethylphenol (1 equiv) CH CH CN CN TMSCN (3 equiv) 3 2 room temp., 48h N3 CH3CH2CN R = 4-Nitrobenzoyl room temp., 95h R = 3,5-Dinitrobenzoyl 85% i.y., 82% ee 96% i.y., 91% ee

Ph O Ph P O O HO Ligand: NHAc O F

HO F EtO2C NH2•H3PO4 Tamiflu

Y. Fukuta, T. Mita, N. Fukuda, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128, 6312. T. Mita, I. Fujimori, R. Wada, J. Wen, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2005, 127, 11252. Enantioselective Opening of Aziridines

OSiMe TMSCN (1.0 equiv) 3 O Conditions 25°C CN

2 mol% Catalyst, CH2Cl2 : 100% conv., 77% ee (2h) 0.01 mol% Catalyst, neat : 100% conv., 56%ee (4h) R

R N O Catalyst (dimer): Y O N O N R

NO2 R

TMSN3 (3.0 equiv) TMSCN (3.0 equiv) NH(CO)Ar Catalyst (10 mol%) Catalyst (10 mol%) NH(CO)Ar

DCE, 25°C DCE, 25°C N N 72h 72h CN 3 O 99% i.y., 97% ee 87% i.y., 94% ee

B. Saha, M.-H. Lin, T. V. RajanBabu, J. Org. Chem. 2007, 72, 8648. B. Wu, J. C. Gallucci, J. R. Parquette, T. V. RajanBabu, Angew. Chem. Int. Ed. 2009, early view. Asymmetric Opening of Aziridines with chiral Acids

Acid: R O H N Acid (10 mol%) R N Ar TMSN3 (1.0 equiv) Ph O O R P CF3 DCE, room temp O Ph O OH 21-91h R N3

F3C 12 examples 49-97% yield (70-95% ee) (1.5 equiv)

E. B. Rowland, G. B. Rowland, E. Rivera-Otero, J. C. Antilla, J. Am. Chem. Soc. 2007, 129, 12084.

iPr iPr 3 Acid: R -OH (4.0 equiv) Ph Ph Cl 3 Acid (15 mol%) R1 R OR N 1 i R 2 1 Pr Ag2CO3 (0.6 equiv) R R O O Ph N R N P 4Å MS, PhCH3, 50°C Ph O OH R2 R2 iPr 24-36h (meso) 11 examples 56-95% yield (90-99% ee) iPr iPr

G. L. Hamilton, T. kanai, F. D. Toste, J. Am. Chem. Soc. 2008, 130, 14984. N-Functionalization of Aziridines

Reactivity of Amines: O OH 1 3 1 + H O 1 1 R H R H R 2 R NaCNBH3 R N N R3 N R3 N R3 − H2O R2 R2 R2 R2

Reactivity of Aziridines:

O R1 R1 R1 R3 H OH N H N N R3 R3 R1 R1 R1 isolable (highly strained)

I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39, 194. Palladium Catalyzed Allylation of Aziridines

Cl Pd Pd (1 mol%) Ph Cl OAc (R)-BINAP (4 mol%) NH + N THF, room temp. Ph Ph Ph 97% i.y., 97% ee

Results obtained with PPh3 as ligand (ratio = linear : branched) :

N

45 % Ph N N

Ph N O 80% (12:88) 99% (92:8) 79% CO2Me MeO2C

N Ph N N 64% 84% 89% i.y. (0:100)

I. D. G. Watson, S. A. Styler, A. K. Yudin, J. Am. Chem. Soc. 2004, 126, 5086. Palladium Catalyzed Allylation of Aziridines

Bn N PdL NH BnNH2 N L = (rac)-BINAP kinetic product thermodynamic product

Possible explanations: N H • pKa difference • product inhibition

N N Pd thermodynamic product

Monitoring the reaction over time:

0 OAc Pd / BINAP NH N N Pd0 / BINAP re-insertion kinetic product thermodynamic product

I. D. G. Watson, S. A. Styler, A. K. Yudin, J. Am. Chem. Soc. 2004, 126, 5086. I. D. G. Watson, A. K. Yudin, J. Am. Chem. Soc. 2005, 127, 17516. Palladium Catalyzed Allylic Amination

Ph NH [(allyl)PdCl]2 (1 mol%) 2 [(allyl)PdCl]2 (1 mol%) Ph N P(OEt)3 (4 mol%) P(OEt)3 (4 mol%) + no DBU (1 equiv) Ph N THF, room temp. THF, room temp. H OAc no isomerization !

R R R RNH 2 R R N N 0 R X − Pd L2 Pd − RNH2 PdL2 X H H L L H H thermodynamic product 0 (linear) Pd L2

L RNH2 R R

Pd 0 R X − Pd L2 N L H H X kinetic product (branched)

I. Dubovyk, I. D. G. Watson, A. K. Yudin, J. Am. Chem. Soc. 2007, 129, 14172. Cycloamination Reactions of Aziridines

O O O CO2H H H2N MeO N O N O H H N O O HN O N NH H O H2N HO H Azinomycin A Ficellomycin

Concept: Cycloamination

Br H N NBS KOH N N

G. Chen, M. Sasaki, X. Li, A. K. Yudin, J. Org. Chem. 2006, 71, 6067 I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39, 194. Cycloamination Reactions of Aziridines

H NBS (1.2 equiv) H DME/H O, 0°C R2 2 R2 R1 R2 2h N or H N H N or Br NBS (1.1 equiv) H Br 1 1 R CH2Cl2, 40°C R 24h R1 = H, alkyl R1 = aryl

H H H COPh H COPh

N N N H COPh Br H Br Br Ph 98% (d.r.: 74:26) 68% (d.r.: > 99:1) 67% (d.r.: 81:19) H H COPh COPh

N H N H H H

HOH2C Br Br 51% (d.r.: 67:33) 51% (d.r.: 67:33)

G. Chen, M. Sasaki, X. Li, A. K. Yudin, J. Org. Chem. 2006, 71, 6067 Cycloamination Reactions Transition State

H H COPh H COPh COPh N H N COPh N N H H Br Br 98% (d.r.: 74:26) 68% (d.r.: > 99:1) H H H H N H N COPh Br COPh Br H 1,3-interaction

H H COPh COPh KOH N N H 1% MeOH in THF H room temp., 30 min R R Br 99% R = H, Me

G. Chen, M. Sasaki, X. Li, A. K. Yudin, J. Org. Chem. 2006, 71, 6067 Cycloamination Reactions and Follow-Up Chemistry

H H H DIBAL-H R R H O N Ph N Ph H R N Ph

NH2NH2 Pd, H2 KOH

H H O O NuH 1) NBS R 2) KOH N Ph N O H Ph R = H, Me Nu R Ph N 1) NBS H H 2) KOH O O 1) Debromination H R R = Ar N Br H Ph 2) NuH, Acid Ar N Ph H Ar Nu

NH2NH2 "Aziridine relay" KOH

H

N Ph PhOC H I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39, 194. Cycloamination Reactions and Follow-Up Chemistry

H H H DIBAL-H R R H O N Ph N Ph H R N Ph

NH2NH2 Pd, H2 KOH

H H O O NuH 1) NBS R 2) KOH N Ph N O H Ph R = H, Me Nu R Ph N 1) NBS H H 2) KOH O O 1) Debromination H R R = Ar N Br H Ph 2) NuH, Acid Ar N Ph H Ar Nu H H NH2NH2 "Aziridine relay" N N KOH

N H Br H Ph Ar N Ph PhOC H I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39, 194. Aziridinoaldehydes - Kinetic Amphoters

O O O DIBAL-H H+ H OMe H -78°C, Toluene N N N H H N H

OH O O O H O H HN N N NH3 H H orthogonal reactivity thermodynamic 76% i.y. kinetic amphoter amphoter (zwitterionic) • stable to racemization • water-soluble

R. Hili, A. K. Yudin, J. Am. Chem. Soc. 2006, 128, 14772. A. K. Yudin, R. Hili, Chem. Eur. J. 2007, 13, 6538. Aziridinoaldehydes - Kinetic Amphoters

OH H N O H DIBAL-H (2 equiv) 1 O R HN N H -78°C, Toluene H H H 1 OEt R H R1

OH

O H OH OH O O HN N H Ph H H Ph H HN N HN N Ph Ph H 83% OH 81% 76% OH O H O H HN N H H S HN N H H H OTBDMS S H TBDMSO 92% 94% R. Hili, A. K. Yudin, J. Am. Chem. Soc. 2006, 128, 14772. Aziridinoaldehydes - Reactivity OH

HN H NaBH4 H Ph 99% OH O O H HN H HN N H H H Ph H H Ph Ph Ph HN Aniline NaCNBH3 HN H H Ph 99%

R. Hili, A. K. Yudin, J. Am. Chem. Soc. 2006, 128, 14772. Aziridinoaldehydes - Polyheterocycle Synthesis

N Bn Bn Bn H H H H N H N H O H N (1 equiv) H H H H Δ Ph Ph Ph TFE N or cat. H2O N HN 0°C, 3h N H N H H H (Dimer) (syn) (anti) 0°C: 97%, (syn/anti = 8:1) −20°C: 94%, (syn/anti = 20:1)

Bn Bn Bn H H H N Ph N H N H H OTBDMS

N N N N H N H N H H H H 81%, (syn/anti = 2:1) 74%, (syn/anti = 1.5:1) 94%, (syn/anti = 3:1)

R. Hili, A. K. Yudin, J. Am. Chem. Soc. 2006, 128, 14772. Polyheterocycle Formation - Mechanism

H Ph N N H Ph H H H Ph N NHBn H H Ph O H N H N N N H H H Ph N H H

Bn H N H H Ph N N H H

Bn Bn Ph H H N H N PhSH H SPh 5 mol% Zn(OTf)2 Ph N NH CH2Cl2, 23°C, 1h N H N H H H R. Hili, A. K. Yudin, J. Am. Chem. Soc. 2006, 128, 14772. A. K. Yudin, R. Hili, Chem. Eur. J. 2007, 13, 6538. Conclusion

• The direct aziridination of olefins is more difficult than the corresponding epoxidation

• A general solution towards an enantioselective ring-opening of aziridines does not exist

• Partial solutions have been discovered over the past 10 years but they are very specific

• Aziridines react different than amines in N-allylation reactions (under the same conditions)

• Cycloamination of aziridines leads to building blocks for heterocycle chemistry and natural products

• Aziridinoaldehydes are kinetic amphoters with unique reactivity

Literature:

Aziridines and in (Ed.: A. K. Yudin),Wiley-VCH, Weinheim, 2006. A. K. Yudin, R. Hili, Chem. Eur. J. 2007, 13, 6538. I. D. G. Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39, 194. M. Pineschi, Eur. J. Org. Chem. 2006, 4979. A. Padwa, S. S. Murphree, ARKIVOC 2006, 3, 6. J. B. Sweeney, Chem. Soc. Rev. 2002, 31, 247. H. M. I. Osborn, J. Sweeney, Tetrahedron: Asymmetry 1997, 8, 1693. D. Tanner, Angew. Chem., Int. Ed. Engl. 1994, 33, 599.