Catalytic Enantioselective Aziridinations

MacMillan Group Meeting April 14, 2004 Sandra Lee

Key References: General Reference: Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247. Metal Catalyzed Aziridinations: Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905. Synthetic Applications: (1) McCoull, M.; Davis, F. A. Synthesis 2000, 10, 1347. (2) Zwanenburg, B.; ten Holte, P. Top. Curr. Chem. 2001, 216, 94.

General Properties of Aziridines

■ How are they different from other secondary amines?

Weaker basicity than alkylamines but stronger than arylamines (aziridinium ion has a pKa of 7.98) Bond strain gives a higher barrier of inversion at N than in acylic amines preventing racemization at RT. most acylic amines ~20 kJ mol-1 for N-inversion 2-methylaziridines is ~70 kJ mol-1 1-chloro-2 methyl aziridine (N-substitution with an EWG) is 112 kJ mol-1 ■ "Epoxides' ugly cousin?"

Epoxides and aziridines are both three-membered heterocycles with comparable Bæyer strain (111kJ mol-1) Difference lies in the additional valency and less electronegative heteroatom in aziridines make them less reactive in corresponding reactions for epoxides

■ Nature of the N-substituent Activated aziridines refer to substitution with an EWG (e.g. acyl, carbamoyl, sulfonyl, sulfinyl, phosphoryl, phosphinyl), protonation, or addition of a Lewis acid to mask the N-H bond in simple aziridines.

1 1 R O R1 LA R R1 X LA O X R1 LA O X O X LA N N O N N N not R R R R R R R1= H, alkyl

ring strain prevents resonance interactions interaction with Lewis acid (LA) to non-bonded electron pairs

Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247.

1 Biologically Active Aziridines

■ There are several classes of aziridine containing natural products that are potent and selective from the inherent specific alkylating ability of aziridines

Nitrogen Mustard Mistosanes Similar to 'mustard gas' and (extracted from steptomyces verticillatus) acts by DNA alkylation demonstrate anti-tumor and antibiotic Cl Cl activity that act by DNA alkyation N Me O O NH2 X OH O Cl- FR and FK Compounds Cl N Me N NH demonstrate anti-tumor activity Me O by DNA cleavage Mitomycin A: X = OMe, Y = Me, Z = H Mitomycin B: X = OMe, Y = H, Z = Me OCONH2 OR1 Mitomycin C: X = NH2, Y = Me, Z = H Porfiromycin: X = NH , Y = Me, Z = Me Azinomycin 2 OR2 (extracted from steptomyces grieseofuscus) O NR3 PBI demonstrate anti-tumor activity R N demonstrate anti-tumor activity that act by DNA crosslinking by single strand DNA cleavage FR- 9000482: R = CHO, R1 = R2 = R3 = H 1 2 3 Me O FR- 66979: R = CH2OH, R = R = R = H FR- 70496: R = CHO, R1= Me, R2= H, R3 = Ac O O R O 1 2 3 H FK- 973: R = CHO, R = R = R = Ac HO N O N FK- 317: R = CHO, R1= R2 = R3 = Ac O N N H NH2 O Me AcO N Me N O Me MeO H PBI-A: R = OAc Azinomycin A: R = H PBI-B: R = OCONH2 Azinomycin B: R = CHO PBI-C: R = H Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247.

General Reactivities of Chiral Aziridines

■ Stereoselective Ring Openings Hydrogenolysis: Pd(OH) , H 2 Nuc C-2 substitution: 2 2 Nu or HNuc R1HN * * often in cases C-2 attack where R = Ar or R1 R Reductive ring opening: SmI2 under chelation N 1 control Hetero nucleophile ring opening: need 3 2 * * activated system for N, S, or Br add'n R R C-3 substitution: Nu or HNuc * * Nu 3 usually Carbon nucleophile ring opening: C-3 attack 1 main product organocuprate add'n, MIRC NHR

■ Ring Expansions ■ Azomethine Ylids Ph 4-membered rings: β-lactams from Ph aziridinecarboxamide N Δ EtO2C N H 5-membered rings: imidazolines, oxazolines, EtO2C CO2Et CO Et and oxazolidinones 2

6-membered rings: aza-[2,3]-Wittig of vinyl aziridines ■ Chiral Ligands Ph Ph Ph 7-membered rings: aza-[3,3]-Claisen of Ph vinylaziridines OH (CH2)n N Tr with Zn or B with Cu

Ph Ph

McCoull, M.; Davis, F. A. Synthesis 2000, 10, 1347.

2 Summary of Methods Used to Access Asymmetric Aziridines

1 1 Br R (R = CO2R )

R1 NHX XHN R Br HO R + - H2NX Cl R4P X R1 S Cl O , RSO2Cl

X ML R1 n NHX PhI=NX, MLn N R1 R R R1 R

H2NX Cl 1 Cl , [O] R 1 S R OH MN3 YR O 2 R PPh3 XHN HO R

R1 R

Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247.

Strategies for Accessing Asymmetric Aziridines

■ Nitrene Transfer to Olefins

X R1 R3 MLn* N R1 R2 X N R3 R2

M = Cu, Rh, Cu, Mn, Ru

■ Carbene Addition to Imines

R R N N C or C + R1 R1 Z R1 Y R2 R2 Y X R2 X

Metallocarbene Addition

Lewis Acid Catalyzed Aziridination

Chiral Sulfonium Ylides

Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.

3 Progress Towards Enantioselective Aziridination

1967 1974 1982 1983 1984 1991 Kahn Baret Breslow and Gellman Mansuy Evans Cu(I)/ TsN3 Cu powder Fe or Mn porphyrins Catalytic Catalytic ethyl diazoacetate or [Rh2(OAc)4] Fe or Mn Enantioselective using TsN=IPh porphyrins [bis(oxazoline)]Cu complex Groves and Takahashi (porphyrine)Mn-imido complex

1992 1993 1995 1996 1999 2003 Pirrung Jacobsen Wulff He Catalytic Catalytic Catalytic Catalytic Enantioselective Enantioselective Enantioselective Disilver(I) Rh(II) [bis(oxazoline)]Cu LA-VAPOL complex Complex Complex complex and with diazoacetate diazoacetate Jacobsen Che Catalytic Templeton Ru(VI) and Ru(II) Enantioselective and Brookhart Diimine-Cu LA and complex diazoacetate Aggarwal Catalytic Enantioselective Sulfonium Ylide Addn

Strategies used are denoted by color blue: nitrene add'n to an olefin red: carbene add'n to an imine Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.

Cu-catalyzed Aziridinations: Evans and Jacobsen Complementary Methods

■ Yields of aziridines are in the range of 25-95% using 5-10% catalyst and upto 5-fold excess of olefin over PhINTs

■ Evans: Bis(oxazoline) Ligand System for Trans Olefins

Ts Me Me Ar O O Cu(OTf), Ligand Ar N Ligand = N N R PhINTs R R' R'

olefin ligand (R' =) yield ee

phenyl cinnamate Ph 64% 97% trans-methyl styrene t-Bu 62% 70% styrene t-Bu 89% 63%

■ Jacobsen: Di-imine Ligand System for Cis Olefins Ligand = Ts Ar R H H Cu(OTf), Ligand Ar N R Cl N N Cl 1 R PhINTs R1 Cl Cl olefin yield ee

Ar = Ph, R1 = Me, R = OTBDPS >95% 27% cis-methyl styrene 79% 67% styrene 79% 66% Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.

4 Jacobsen's Proposed Mechanism of the (Diimine)copper-Catalyzed Aziridination Ts + - Ar N R L*Cu PF6 L* = R1 PhI=NTs H H Cl N N Cl Ar R PhI Ts Cl Cl 1 - R *LCu N PF6 I+Ph or + - L*Cu=NTs PF6

■ Poor selectivity in non-aromatic alkenes 2.99 Å X-ray structure of L*Cu-styrene complex shows that there are 2 non-bonded interactions 3.26 Å 1) face-face interaction and 2.94 Å 2) edge-face interaction of the arenes

■ Discrete Metal-nitrene Complex Ts hν L*, CuPF6 N L*, CuPF6 TsN3 [TsN] PhI=NTs Ph -N2 10 °C, Ph 10 °C, Ph 41 %ee DFT studies support a copper-bound sulfonyl nitrene and additional oxygen coordination in the reactive intermediate H O N Cu S O Ar Li, Z.; Quan, R. W.; Jacobsen, E. N. JACS 1995, 117, 5889. Quan, R. W.; Li, Z.; Jacobsen, E. N. JACS 1996, 118, 8156.

Nitrene Transfer from in the Cu-catalyzed Asymmetric Aziridination

■ Stereospecific azirdination may occur via a singlet metallonitrene complex and nonspecific aziridination through the triplet state metallonitrene complex

L*Cu

N O N concerted NSO2Ar Cu S + O Ar R Ar H H R Ar

R Ar

singlet reacts stereospecifically

L*Cu NSHO2Ar N L*Cu Ar R stepwise N + H H H H Ar NSHO2Ar R Ar R Ar R triplet radical clock does not react experiments were stereospecifically inconclusive in because diradical may determining a undergo bond-rotation radical intermediate ■ DFT calculations by Norrby and Andersson indicate that the ground state of the metallonitrene is in the triplet state (but energetically close to that of the singlet state by 0.1 kcal mol-1)

Brandt, P.; Södergren, M. J.; Andersson, P. G.; Norrby, P.-O. JACS 2000, 122, 8013. Li, Z.; Quan, R. W.; Jacobsen, E. N. JACS 1995, 117, 5889. Sweeney, J.B. Chem. Soc. Rev. 2002, 31, 247.

5 Norrby's Mechanistic Studies of the Cu-catalyzed Azirdination

■ Potential free energy surface of a model system (BSIII/298K)

s = singlet s: 0.0 us = unrestricted 0 t singlet N N O (estimated N free energies) -10 N O s: -20.7 Cu S N t = triplet Cu t: -26.3 -20 N O R Cu S N N s: -33.9 N -30 s: -37.5 N O R Cu t: -39.0 t: -45.1 Cu -40 IPh us: -45.1 us: -44 N N O N Bar N N N O rierle -50 c ss a Cu S s: -55.2 N lose ddit N O Cu S d sh ion o ell s n th O R ingl e N -60 Cu S O R et su N rface O R s: -69.5 -70 N

Cu-Alkene Free Cu- Cu-PhINTs Cu-Nitrene TS: Intermediate TS: Cu-bound Complex Ligand Complex N-C bond C-Centered Ring Aziridine Complex fomation Radical Closure Product

■ Kinetic Studies Computational studies indictate the rate-determing step to be the formation of the Cu-nitrene (0th order N N N PhINTs in alkene) Cu Cu Cu NTs k N N 1 N Observed 1st order reaction with with intial rate dependence on alkene concentration proportional to NTs metal concentration k2

N Müller examined electronic substituent effects on Cu NTs substituted styrenes and observed a ρ-value -0.49 N (vs σ+), which is in the range for concerted carbene transfer to olefins Andersson, P. G.; Norrby, P.-O. JACS 2000,122, 8013. Müller, P. Can. J. Chem. 1998, 76, 738.

Other Ligand Systems Developed for Cu-catalyzed Asymmetric Aziridinations

H Cl

O Me Ph H Cl N X N Me Cu Me Me N H H N N O N O Me (Cp2)Fe Me Cu Me Fe(Cp2) H Ph Me N X = O, N-p-Tol Cl Masamume (1991) Kim (1999) Andersson (1998) for styrene: for styrene: for styrene: Cl 91 %yield 88 %yield X = O: 90% yield, 24 %ee 88 %ee 74 %ee X = N-p-Tol: 100% yield, 15 %ee *not reproduced* Scott (2002) for styrene: 91 %yield 27 %ee Me Me Me N F C CF3 CF Me 3 B 3 N N N O CCF 2 3 N N Cu Cu N N O N O2CCF3 N N N Me Cu O CF3 Me Me F3C CF3 CF3

Halfen (2001) Halfen (1999) Dias and Lovely (2002) for styrene: for styrene: for styrene: 99 %yield 99 %yield 99 %yield

Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.

6 Manganese-Catalyzed Aziridinations

X R Mn-catalyst N

Ph Ph R

■ Nitridomanganese(V) Complexes Activation (by BF , TsCl, or TFAA) generates an manganese nitrido 3 H H complex where to transfer the imido group to the olefin N N N Komatsu demonstrated that conjugated dienes underwent [2+1] Mn add'n to form alkenylaziridines (no [4+1] products were observed) t-Bu O O t-Bu

Ho and Wong formed the free aziridine of styrene ( 36 %yield, 81 t-Bu t-Bu %ee) and trans-β-methyl styrene (20 % yield, 91 %ee). ■ Manganese(III) Porphyrin-based Catalysis with TsN=IPh Me H Me CO2Me

OH Me Me Me Me N Cl Me N N N O Mn Ph + Mn Mn N O N Ph N N N O H Me CO2Me MeO2C H Me Marchon (1999) Katsuki (1996) Che (1997) for styrene: for styrene: for styrene: 34 %yield Me MeO2C 76 %yield 73 %yield 57 %ee H Me 94 %ee 55 %ee

Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.

Origins of Diastereoselectivity and Enantioselectivity in Mn-Catalyzed Aziridinations

■ Yield and level of asymmetric level induction in azirdination is lower than in epoxidation

Me Me Olefin approach to Me Me Impeded olefin oxo-metal bond for approach to N- epoxidation in Ts sulfonyl metal N N open space N N bond for aziridination O N O O O O PhPh PhPh

Mn(III) =

■ Enantioselectivity is considered to be steric repulsion of the C8 or C9' substituent, the N- sulfonyl group and the olefinic substituent

Conformation A and B allow for olefin approach to maximize the π-orbital of the oncoming olefin and dπ-pπ* orbital of the nitrene metal bond

Me Me Me Me Ts 8 8' 8 8' b N N N N N a N O O O O Ts PhPh PhPh 9 9' 9 9'

conformation A conformation B Katsuki, T.; etal. Synlett 1993, 469.

7 Ruthenium-Catalyzed Aziridinations

■ Ruthenium(VI) Porphyrin Complex Ph Ruthenium counterparts of Mn-porphyrin aziridinating reagents have only been isolated and characterized recently NTs N N Mechanism is assumed to be via a stepwise via a radical Ph Ru Ph intermediate and thus is not stereospecific N N NTs Ts Ru(VI)-catalyst N Ph Ph Ph 75 %yield *stoichiometric* ■ Ruthenium(II) Diimine Complex Limited substrate scope only for cyclic substrates and reaction is proven to be better suited to amidation than aziridination

H H PPh N 3 N Ts O R Ru(II)-catalyst N Ru R NTs R1 O O 1 2 PPh R R TsN=IPh 1 2 3 R R R2 X X R = H; X = NO2 R = OTMS; X = Br 68 - 84 %yield 73 - 83 %yield X = NO , Br 45 - 83 %ee 58 - 97 %ee 2

Che, C.-M.; etal. JACS 1999, 121, 9120. Che, C.-M.; etal. Chem. Commun. 2002, 124.

Rhodium(II)-Catalyzed Aziridinations

X [Rh2L*4] N

Ph R NsN=IPh Ph R

■ Issues of competing C-H insertion reactions and O electron-rich olefins can often give ring opened/ O Pirrung (1992) cycloaddition products (ie. pyrrolidines) P R = H: 74 %yield, 55 %ee O O Me: 80 %yield, 73 %ee

■ Rh is less efficient at trapping nitrene than Cu,using Pirrung's catalyst, TsNI=Ph gives a 55 ee% in the O Doyle (1999) aziridination of styrene and TsN gives a 17 %ee 3 R = H: 71 %yield, 27 %ee O N CO2CH2Ph Me: 70 %yield, 35 %ee ■ Guthikonda and Du Bois are able to aziridinate alkyl and aryl substituted olefins using an in situ derived phenyliodinane and trichloroethylsulfamate

NSO3CH2CCl3 NSO3CH2CCl3 95 %yield Me substrate scope styrene derivatives: includes: Rh2(CF3CONH)4 71-95 %yields 72 %yield n-Hx NSO3CH2Cl3 terminal, cis and Me trans,cyclic and PhI(OAc)2, MgO 83 %yield NSO3CH2CCl3 NSO3CH2CCl3 trisubstituted olefins H2NSO3CH2Cl3 Me Me Me n-Hx

72 %yield OAc 57 %yield

Müller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905. Guthikonda, K.; Du Bois, J. JACS 2002, 124, 13672.

8 Catalytic Disilver(I) Aziridination of Olefin

■ A promising new unique di-nuclear silver catalyst Ag-catalyst = O 2 R N t-Bu Ts Ts Ag-catalyst (2 mol%) t-Bu O O R1 N R2 or N or N t-Bu PhINTs N Ag R1 R1 R2 N R1 R2 t-Bu N Ag N N olefin yield

t-Bu styrene 91% t-Bu trans-methyl styrene 89% R1 = alkyl, R2 = H 66 - 71% R1, R2 = Ph (trans) 88% R1, R2 = Ph (cis) 86%

Each of the silver ions of the dinuclear complex is a 5-coordinate and stabilized two bridging tridentate terpyridine ligands

X-ray structure of the catalyst shows two terminal positions (one weakly bound by a nitrate anion)

Reactivity is assumed to be from electronic communication between the silver ions (Ag-Ag distance is 2.842 Å) with an assumed transient Ag=NTs group coordinated to the active aziridinating agent

Cui, Y.; He, C. JACS 2003, 125, 16202.

Aziridination via Metallocarbene Addition to Imines

■ Initial azirdinations with diazoacetates (with Rh(II), Mn(III), Cu(I)) were plagued by poor yields and racemic products (due to the formation of Me Me intermediary ylides) L* = O O N N

■ First enantioselctive aziridination of imines was by Jacobsen (1995) t-Bu t-Bu

■ Jørgensen (1999) has shown that tosyl aziridines can be generated using TMS-diazomethane with CuL*

Ph CO2Et CO2Et Ph H CO2Et CuPF (MeCN) , L* N 6 Ph CO2Et N + + + N N N Ph 2 Ph Ph Ph Ph EtO C CO2Et 30 %yield 2 7 %yield 10 %yield mechanism: 44 %ee 35 %ee

optically active CO Et aziridine 2

EtO C L*Cu EtO2C 2 + - H CO2Et CO2Et - L*Cu Pf6 H N H N CuL* + - Ph Ph PF6 + L*Cu Pf6 Ph Ph Azomethine Ylide Leads to racemic azirdine products

Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. ACIE 1995, 34, 676. Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Chem. Soc., Perkins Trans. 1 1999, 2293.

9 Lewis-Acid Catalyzed Aziridination of Imines

H CO2Et + N2 CO2Et CO Et Ph Ph 2 LA N2 N N Ph N N Ph Ph LA Ph Ph LA Ph

■ Brookhart and Templeton (1996) used BF3, AlCl3, and TiCl4 with yields of 42 - 93 % yield. A wide range of LAs have been used in aziridinations of imines

■ Wulff (1999) had a breakthrough using (S)-VAPOL and BH3 to generated 'vaulted' an axially chiral boron complex. Previous attempts of testing chiral ligands with zinc triflates and various lanthanide trifates had yielded low ee's

■ Enamines formation was the main side product, however, typical secondary products for carbenoid reactions (diethyl fumarate and maleate) were not observed Ph CO Et Ph 2 H Ph

Ph H CO2Et N N + N + Ph EtO2C H N Ph R 2 R Ph H Ph R = Ph: 77 %yield, 95 %ee n-Pr: 54 %yield, 91 %ee EtO2C Ph Ph O BH t-Bu: 78 %yield, 91% ee N Ph O R H

Other ligands, BINOL or BANOL were less efficient Antilla, J. C.; Wulff, W. D. JACS 1999, 121, 5099. Antilla, J. C.; Wulff, W. D. ACIE 2000, 39, 4518.

Aziridination of Imines via Chiral Sulfonium Ylides

Na+ BOC reaction Ph N N occurs via BOC Ts N Ph nucleophilic S N attack of sulfonyl ylide Ph Rh (OAc) (1 mol%) Ph Ph 2 2 to imine R chiral sulfide (20 mol%)

Me Me Me Me Me Me O O O S Me Chiral H Me S O sulfides: O Me Me S S Me S Me 33 %yield 47 %yield 34 %yield 36 %yield 24 %yield 89 %ee 95 %ee 95 %ee 79 %ee 77 %ee cis:trans=1:8 cis:trans=1:3 cis:trans=1:3 cis:trans=1:3 cis:trans=1:3 ■ Aggarwal (1996): in situ generation of a Catalytic Cycle: carbene via diazo decomposition of a H R' R H stable tosylhydrazone with [Rh2(OAc)4] N S C or [Cu(acac) ], its association to a chiral Rh2(OAc)2 N2CHPh 2 R R Ph sulfide, and transfer to an imine

■ A range of imine N-substitution (tosyl, SES,Dpp, and carbamoyl) are amenable R' to this procedure N Aggarwal, V. K. Synlett 1998, 329. R2S Rh CHPh N2 Ph R Aggarwal, A. K.; Thompson, A.; Jones, R. V. H.; Standen, M. C. H. JOC 1996, 61, 8368.

10 Origin of Diastereoselectivity and Enantioselectivity in Sulfonium Ylide Aziridination

■ Energy difference between the syn- and anti- betaines is under kinetic control Calculations suggest that the sulfur ylide reacts in an "end-on" approach to the N-Ts imine to give rise to transition states A and B.

■ Observed diastereoselectivity varies with H TMS N-substitution: N TMS TMS Ph N N H R H R Larger bulky groups on N leads to Me R reduced trans selectivity S C or Me H Ph H H Ph (sulfonyl or phoshinyl groups) S S Me Me Me Me Smaller groups on N leads to increased trans selectivity A B (alkoxycarbonyl groups) leads to trans- leads to cis- aziridines aziridines (major isomer) ■ Conformer A reacts is favored over conformer B which has unfavorable 1,3- diaxial interactions High facial selectivity is a result of steric (attack opposite the methyl group) and electronic (a combination of the anomeric effect and Ciepak effect) control.

Me Me Me Me

Ph S O H S O Me Me H H H H (R,R) aziridine H (S,S) aziridine Ph conformer A conformer B

Aggarwal, V. K., etal. J. Chem. Soc. Perkin Trans. 1, 2001, 1635.

Conclusion and Future Directions

■ From the first synthesis of an aziridine by Gabriel (1888) was a two step process from an amino alcohol

H H2SO4 KOH N HO NH NH NH or 2 <250 °C O O Δ S S 26 %yield O2 O2

■ Single step methods for accessing aziridines from prochiral substrates has been through metal- catalyzed aziridinations that utilize two general strategies: nitrene addition into olefins or carbene addition into imines ■ Developed catalytic systems (Cu-, Rh-, Mn-, Rh-, Ru-based catalysts) have attained good enantioselectivities but have not been readily translatable to other substrates

Movement is towards newer catalyst systems that have higher enantioselectivities (Agarrwal and Wulff) an higher reactivity (Du Bois and He) that show better substrate scope.