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Catalytic Enantioselective Aziridinations

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Catalytic Enantioselective Aziridinations 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 O FR- 66979: R = CH2OH, R = R = R = H Me 1 2 3 FR- 70496: R = CHO, R = Me, R = H, R = 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 R1 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 O 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 -1 is in the triplet state (but energetically close to that of the singlet state by 0.1 kcal mol ) 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.
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