Mechanism and Application of Salen in Asymmetric Catalysis Mike Brochu MacMillan Group Meeting July 9 2003

Salen Complexes: A Privileged Chiral Catalyst R' R' R R Diverse family of accessible products N N M R O O R

O H OH R R OPh MeO NBz O Ph

O Epoxidations MeO CO tBu Ar OH 2 • H Aziridinations O Ar N3 H Me O Epoxide Ring Opening

Me O O OH SiMe3 Hydrolytic Kinetic Resolution Me N Ph Ph H NHTs O OEt Me N3

SiEt3 OH HN Ph S Me Me SiMe3 Me CN Me O NO2 OH

Reviews and seminal papers:

Katsuki, T. Synlett, 2003, 281 Comprehensive Asymmetric Catalysis, Vol II. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds; Springer: Berlin, 1999 Catalytic Asymmetric Synthesis, Second Edition. Ojima, I. Eds: Wiley-VCH. 2000

Zhang, W.; Loebach, J. L; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801 Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115, 5326

1 Interest Began in Understanding Biological Systems N O N Fe Cytochrome P-450 N N

Critical to hormone biosynthesis, drug metabolism, and detoxification of xenobiotics Suprafamily of cysteine thiolate-ligated heme iron enzymes that activate dioxygen for insertion or addition of a single atom OH

R R' R R' O R R R' R' OH S S R R' R R'

Reactions proceed through cationic oxoiron (IV) species which are generated by the oxidation of Fe(III) with O2 e-

O FeIII P-450 FeII P-450 - e , O2 Shunt Path: PhIO, NaOCl

O2- O O FeIV P-450 FeIII P-450

+ H2O 2 H

Sono, M.; Roach, M. P.;Coulter, E. D.; Dawson, J. H Chem. Rev. 1996, 96, 2841

Porphyrins: Active Site Mimics R* Groves Uses Metalloporphyrins for Epoxidations N O N *R M R* In 1979 Groves found that treatment of Fe(III) complex with terminal oxidant N N provided cationic oxoiron(IV)-porphyrin complexes that epoxidize simple olefins.

In 1983, Groves used a chiral iron porphyrin complex to promote the asymmetric R* epoxidations of olefins

O

A, PhI=O, Toluene 51% ee 63 % yield Cl Cl

Side-on approach Hypothesizes that olefin approach must be side-on in order for stereochemical information to be passed from porphyrin to olefin

O N N Ar M Ar O O H a a O O b H Fe b Presence of aldehyde by-product and low enantioselectivity Ar interpreted as evidence for radical mechanism H O

Groves, J.T.; Nemo, T. E.; Myers, R.S. J. Am. Chem. Soc. 1979, 101, 1032 Groves, J. T.; Nemo, T. E. J. Am. Chem. Soc. 1983, 105, 5786 Groves, J. T.; Myers, R. S. J. Am. Chem. Soc. 1983, 105, 5791

2 Kochi Begins Working with oxo Metal-salen Complexes N N M Successfully isolates oxo Cr-Salen Complex N N

Salen complex designed to mimic porphyrin core sp3 C's now located 2 atoms away from metal center N O N O N O N N O N M Cr O O Cr N N Mn O O O O OTf- - O O - OTf O.53 A PF6 A B

Oxo Cr-salen complex has square-pyramidal structure Unable to isolate oxo Mn species Participates in one oxygen atom transfer to olefins to provide epoxides

A, PhI=O O 85% yield

B, PhI=O O 69% yield

Radical Intermediate is postulated

Samsel, E. G.; Srinivasan, K.; Kochi, J. K. J. Am. Chem Soc. 1985, 107, 7606 Sriniviasan, K.; Michaud, P.; Kochi, J. K. J. Am. Chem. Soc. 1986, 108, 2309

Jacobsen and Katsuki Enter the Game Ph Ph N N Mn First moderately selective epoxidation of O O - unfunctionalized olefins PF6 t-Bu t-Bu A

Olefin Catalyst yield,% ee,% previous best ee,% Ph Ph Me A 50 59 12 H H N N Mn O O AcO- A 72 67 36 H H Ph Ph Et Et B A 73 84 Me 44 Ph B 26 44

A 93 20 16 Ph B 37 44 Me

Side-on approach of olefin is used to explain sense of enantioselection Superior enantioselectivity over porphyrin systems is attributed to chirotopic carbons in vicinity of metal

Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc., 1990, 112, 2801 Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahedron Lett. 1990, 31, 7345

3 Jacobsen and Katsuki Achieve High Levels H H of Enantioselectivity N N Mn modification provides crucial difference t-Bu O ClO t-Bu

A t-Bu t-Bu

Olefin Catalyst yield,% ee,%

A 81 92 Ar Ar Me Ph B 16 90 N N Mn O O O Me A 72 98 Ar Ar Me B 60 >99

B AcO-

O A 63 94 O

CO2Me A 65 89 Ph

B 82 94

Axially locked substituents on diimine bridge lead to more effective differentiation of olefin approach Locking the diimine bridge provides opposite sense of asymmetric induction

Increased steric bulk at C3 and C5 enhances enantioselectivity

Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063 Sasaki, T.; Irie, R.; Hamada, T.; Suzuki, K.; Katsuki, T. Tetrahedron 1994, 50, 11827

Debate over Approach of cis-Olefins

Side-on approach is accepted model for oxo M-porphyrin and oxo M-salen complexes

Side-on approach top-on approach

N O N M N O N O O M O O First and second generation ligands discriminate olefin approach differently

Ph Ph RL a 1" 2" N O N R Mn RL RS S O O - RL 3 PF6 3' b t-Bu t-Bu RS c H H R Ph Ph N O N a L 1" 2" a RL Mn N O N t-Bu O ClO t-Bu RS Mn R O O S t-Bu t-Bu - 3 PF6 3' H H Ph Et Et Ph

Side-on approach allows for approach of incoming olefin by three pathways with second generation ligand

4 Jacobsen Rules Out Approach A for his Second Generation Ligand Ph Ph Ph H a N O N Argument is solely based on sterics Mn Me O O Me Me H PF - (favored) 6 t-Bu t-Bu 1 cat. (5 mol %) Ph Me Ph Me NaOCl(aq) DCM O Ph Me H H b (favored?) Catalyst R1 R2 yield, % ee, % epoxide confign

1 N/A N/A 88 84 1R,2S-(+) 1 1 R R H Ph O 2 Me Me 54 49 1S,2R-(-) N N a Mn R2 O O R2 2 Me t-Bu 56 55 1S,2R-(-) Cl H Me

2 H Me 87 80 1S,2R-(-) t-Bu t-Bu 2 2 H t-Bu 81 92 1S,2R-(-)

Catalyst 2 is less hindered than 1 in the vicinity of approach b Replacement of Me groups at R1 with H further opens approach b Increasing steric bulk at R2 (Me v. t-Bu) partitions olefin approach away from path a

Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063

What Factors Contribute to Enantioselectivity? H H Sterics alone do not explain enantioselectivity N N Mn 1 1 R O ClO R Electronic variation on substrate and ligand have pronounced effect 2 2 on enantioselectivity and yield A R R

Entry Olefin R1 R2 Yield(%) ee (%)

1 NO2 t-Bu 46

2 Me t-Bu 80 Me electronic variation

3 P h OMe t-Bu 86 on ligand

4 t-Bu t-Bu 90

5 t-Bu t-Bu 81 92 Me

6 t-Bu t-Bu 50 Me electronic variation TMS on substrate 7 t-Bu t-Bu 65a 98

TMS 8 t-Bu t-Bu 34a 35

aEpoxide exists as a mix of cis and trans isomers. C H : 5.2:1, C H : 1:1 6 11 6 5 Katsuki, T. Coord. Chem. Rev. 1995, 140, 189

5 RL

Katsuki Proposes a New Method of Olefin Approach RS c H H Electronic influence on olefin approach N O N Mn R O ClO R

A linear correlation between ee and substituent sigma value indicates that t-Bu t-Bu substuent effects are electronic as well as steric.

1.8 1.2 0.4

1.6 0.35

) 1 s r 1.4 e 0.3 m o i t 1.2 0.8 n

a 0.25 n e

1 f o 0.6 0.2 o i

t 0.8 a r ( 0.15 g 0.6

o 0.4 l 0.1 0.4 0.2 0.2 0.05

0 0 0 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

Hammett value O Hammett value Hammett value Ph Me t-Bu Et Olefins approaching along path c experience different electronic environments on different side of M-N axis

O H O H Mn Mn R R

salicaldehyde part cyclohexyl part salicaldehyde part cyclohexyl part

Repulsive pi-pi electron interaction between the ring of the and the substituent are important

Hamada, T.; Irie, R. Katsuki, T. Synlett. 1994, 479 Katsuki, T. Coord. Chem. Rev. 1995, 140, 189

Jacobsen Proposes a Different Interpretation Ligand electronics modulate the reactivity of (salen)Mn oxo intermediate H H Electron-donating groups lead to a less reactive (salen)Mn oxo intermediate, N N Mn which results in a comparatively late transition state 1 1 R O ClO R

R2 R2

Since the transformation involves the encounter of two reactants which do not resemble each other at the origin of the reaction coordinate, more stereochemical communication can be passed in a later transition state

-0.02 6 sp2 -0.03 O 5.5

Chart 1 y t Chart 1 V i 5 Chart 2 v

-0.04 Ph D i + M t c

e 4.5 l D

-0.05 e k L / s

4 H l k a

-0.06 i g c 3.5 o a l f o Ph i

-0.07 t 3 n

D a

n 2.5 -0.08 2 3 sp sp e 2 -0.09 O 1.5 MIV -0.1 1 -0.4 0.1 0.6 L 0.8 0.85 0.9 0.95 1

hammett value kH/kD The electronic character of the catalyst alters the degree of rehybridization of the ß-carbon and thus the position of the transition state (chart 1) Late transition states in the C-O bond forming step affords higher enantioselectivity in the epoxidation reaction (chart 2)

Palucki, M.; Finney, N. S.; Pospisil, P. J.; Guler, M. L.; Ishida, T.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 948

6 Case of 1-methylindene N O N Mn Experimental Results do not fit model R2 O O R2 - PF6 R1 R1 Trans:cis ratio should improve with added steric bulk at R1 and R2

O catalyst, PhI=O O

Me Me Me A B

R1 R2 A:B

H H 3:1 t-Bu H 5.7:1 t-Bu t-Bu 6.2:1

Is there a better model?

L 2 O S R N N Mn O O R1 1 R R2

Salen ligand adopts a non-planar stepped conformation

Noguchi, Y.; Irie, R.; Fukuda, T.; Katsuki, T. Tetrahedron Lett. 1996, 37, 4533

The Folded Structure R R O Explains sense of induction N N Mn 2 2 R O L O R Salen complex exists in a equilibrium of two conformers which is 1 controlled by axial and equitorial considerations of R groups R R1 on diimine bridge

R R L 2 O R S O R2 R N N N N Mn Mn O O O O R1 R R1 L 1 1 R R2 R2 R L Steric Repulsion

Olefin passes over benzene ring in the down position, thereby avoiding interaction with bulky group at R2

Oxo M-salen is known to exist in a non-planar, stepped conformation

Kochi initially isolated an oxo(salen)chromium (V) complex as well as its N-oxide adduct and crystal structures of both species show a stepped comformation

Oxo Cu(salen) complexes isolated in aziridinations are folded

Noguchia, Y.; Irie, R.; Fukuda, T.; Katsuki, T. Tetrahedron Lett. 1996, 37, 4523

7 Experimental Support for Folded Structure R R R R N N Use of achiral salen complex and a chiral ligand Mn t-Bu O O t-Bu - PF6 Me t-Bu t-Bu O N O Me A, additive O2N O 2 73% ee A Me Me DCM-H2O (30:1) AcHN AcHN O A: R= Me, Additive= (-)-Sparteine: 73% ee COO-

N N Presence of a chiral ligand in oxo Mn(salen) complex makes Mn two conformations diastereotopic O O Ph Ph

Carboxylate group on diimine bridge can lock ligand into one conformer B

Me B: 99% ee, 92%, O2N O B (0.01 mol%) or C (1 mol %) O N O Me 2 TON =9,200 Ar Ar Me Me terminal oxidant AcHN AcHN N N O C: >99% ee, 80% Mn O O

L Ph Ph - 2 O COO S O R2 R N N N N Mn Mn O O O O R1 R1 C 1 1 O R R2 R2 R O Coordination

Hashiyata, T.; Ito, Y.; Katsuki, T. Synlett 1996,1079 B and C gives same sense of enantio-induction despite the opposite Hashiyata, T.; Ito, Y.; Katsuki, T. Tetrahedron 1997, 53, 9541 configurations of moieties on diimine bridge Miura, K.; Katsuki, T. Synlett. 1999, 783 Ito, Y. N.; Katsuki, T. Tetrahedron Lett. 1998, 39, 4325

Mechanism of Oxygen Transfer Mechanism still in controversy H H N O N Mn 1 1 R O ClO R Path A - Direct substrate attack at the oxo ligand with concerted C-O bond formation (i) R2 R2 Path B - Stepwise mechanism characterized by reversible formation of a metallaoxetane prior to epoxide formation either through a radical intermediate (ii) or through metallaoxetane decomposition (iii)

R R Ph Ph O O i MnIV MnV a O ii Ph R MnV R b iii O Ph R MnV Ph O

Ar R Initial evidence for path a Ar R Ar R collapse H H Proposed by Groves and Kochi to explain early work + O O O cis- and trans-epoxides are formed from cis-olefins rotation H R Mn Mn Y collapse Ar H Conjugated olefins are isomerized to a greater extent than Y O unstabilized olefins Mechanistic simplicity

Katsuki, T.; J. Mol. Cat. A 1996, 113, 87

8 Evidence for Path B R R R R R 1. Cyclopropane RAR O M O R Epoxidation of phenylvinylcyclopropanes gives corresponding O M epoxide without cleavage of cyclopropane ring M

Ph Ph Ph R R R Me R rotation Ph Ph Ph path b O O Ph Me epoxide and M M epoxide epoxide epoxide ring opened pdt Rate of rearrangement for phenylcyclopropane is very fast (>1010 s-1)

2. Non-linear relationship between enantioselectivity and temperature

If a reaction involves reversible formation of diastereomeric intermediates and irreversible transformation of the 4 intermediates to a product of another intermediate there is (A) 3 a possibility for a non-linear relationship between (A) )

P

enantioselectivity and temperature ( 2 n l The reversible formation of a metallaoxetane intermediate 1 is a viable explanation for this observation (B) (B) 0 3.3 3.5 3.7 3.9 4.1 4.3 4.5

103 T-1 (K-1) major enantiomer of epoxide 3. Molecular modeling of transition state P = minor enantiomer of epoxide The enantioselectivity of the reaction can be explained by the energy difference between two diastereomeric metallaoxetane intermediates. The intermediate which leads to the major epoxide enantiomer is 11 kcal/mol more stable.

Norrby, P-O.; Linde. C.; Akermark. J. Am. Chem. Soc. 1995, 117, 11035 Katsuki, T.; J. Mol. Cat. A: 1996 (113) 87

R R Evidence Against Path B R R R R M O O Metallaoxetane requires apical coordination site O 1 M M The formation of a metallaoxetane requires a coordination site adjacent to the oxo ligand for the M-C bond, 1 R R R R R rotation Me O O Me A path b R O M M Ph Ph M O X increased ee, rate, conversion and cis/trans ratio 2 H H Axial binding throughout the catalytic cycle implies that the adjacent sites required for N Cl N metallaoxetane are unavailable and the reaction must proceed through a highly Mn strained intermediate 2 O O O O O Jacobsen attempts to reproduce non-linear Eyring plots t-Bu N t-Bu

3.5 O O O O O 3 A ) ) r

o Me n i

m 2.5 Ph k / r o j a m k

( 2

n l

1.5

1 3 3.5 4 4.5 5 5.5 1/T x 103 K-1

Eyring plots for 4 olefins all showed linear behavior

Finney, N.S.; Pospisil, P. J.; Chang, S.; Palucki, M.; Konsler, R. G.; Hansen, K. B.; Jacobsen, E. N. Angew. Chem. Int. Ed. 1997, 36, 1720

9 1 R1 R Salen Ligand Mediated Epoxidation - Scope N N M R2 O O R2 Functional group tolerance R3 R3 R R O O OR R R OR R NR2 R R O ethers esters amides

O R

OSiR3 R O R R NO2 R acetals silyl ethers nitros acetylines Functional group intolerance

R SR R OH sulfides allylic alcohols

Conjugated vs. non-conjugated olefins

R R > R R= alkyl

Terminal Olefins

R1: Ph O 86% ee 4 mol% catalyst 2 88% yield R : OTIPS R3: H mCPBA, NMO, DCM, -78 oC

Salen Ligand Mediated Epoxidation- Scope OH - N Br Olefin geometries N

OMe > > A

N O N Stereochemical induction for trisubstituted olefins is opposite of disubstituted olefins Cr O O

Ph variety of Ph B R halogens on R Ph benzyl ring Ph O O O O Mn Mn Mn Mn

Trans - olefins

4 mol %salen ligand, 20 mol% A O Me Ph Ph 90% ee Me 27:1

B Me O Ph Me >88% ee Ph >80% yield

O'Mahony, C. P.; McGarrigle, E. M.; Renehan, M. F.; Ryan, K. M.; Kerrigan, N. J.; Bousquet, C.; Gilheany, D. G. Org. Lett. 2001, 3, 3435

10 Aziridination N source

Three mechanistically different approaches chiral NH catalyst i - Azirdination via Imido Transfer Catalysis ii - Azirdination via Carbene Transfer Catalysis iii - Azirdination by Lewis Acid catalysis

R" RCH=CHR' N RCH=NR" L M + R"NX L M=NR" n n LnM=CHR' R'CHN2 + LnM R R' i ii N2

N2

"R LA- N R' R + N2

iii Lewis Acid (LA)

RCH=NR" + R'CHN2

Jacobsen, E. N. Comprehensive Asymmetric Catalysis...

Historical Development of Salen Mediated Aziridination R

Groves and Evans provide scientific background N N N R MnV R N N 1983 Groves demonstrated stoichiometric azirdination of by way of in situ generated manganese-nitridocomplex R

COCF3 A N COCF3 A, 1.2 eq. TFAA N proceeds via: + - R R LnM O2CCF3 N N 1992, Burrows reported aziridination using salen ligands, but without enantioselectivity Mn O O

R R Ts B B N 20% yield + PhI=NTs Ph 0% ee Ph O O N N In 1991 Evans discovered that low-valent copper can catalyze aziridinations by way of ligand C R R C Ph Ph Ph

CO2Me Me H

R=Ph R=t-Bu R=t-Bu 63%, 94% ee 62%, 70% ee 86%, 78% ee High levels of enantioselectivites with cinnamate esters, but difficulties with other substrate classes

Groves, J.T.; Takahashi, T. J. Am. Chem. Soc. 1983, 105, 2073 Evans, D.A.; Faul, M.M.; Bilodeau, M.T. J. Org. Chem. 1991, 56, 6744 O'Connor, K. J.; Wey, S. J.; Burrows, C. J. Tetrahedron Lett. 1992, 33, 1001 Evans, D.A.; Faul, M.M.; Bilodeau, M.T.; J. Am. Chem. Soc. 1994, 116, 2742

11 Jacobsen Discovers Cu(salen) Aziridination Cl Cl Offers synthetically useful levels of enantioselectivity N N Cl Cl

A

CuOTf or CuPF6 (5-10 mol%) Ts Ar R" A, (6-12 mol%) N PhI=NTs R R' Ar R" R R'

O Ph Ph CO Me Ph Ph 2 NC Ph

75% 70% 79% 92% ee 94% ee >98% ee 87% ee (3:1 cis:trans) 66% ee cis 81% ee trans

Reaction scope is limited: requires olefin to be in conjugated with aromatic group for high ee

Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115, 5326 Li, Z. PhD thesis, Harvard University 1997

Mechanism of Cu(salen) Catalyzed Aziridination

Two reasonable mechanisms can be postulated Cl N N Cl

Redox Mechanism - Analagous to cyclopropanation mechanism, involves discrete Cl Cl formation of Cu-nitroid intermediate A Lewis Acid Mechanism - Copper complex functions as a Lewis Acid catalyst

Redox Mechanism Lewis Acid Mechanism

+ - 1 3 L*Cu+ PF - L*Cu PF6 R R 6 R1 R3 2 PhI=NTs R N PhI=NTs R2 N Ts Ts + PhI

R1 R3 1 3 PhI R R R2 2 Ts + R L*Cu N [L*Cu=NTs] + - I Ph PF6

Two pieces of evidence for the redox mechanism: t-Bu Ar= Ph Me Me Me A, A, CuPF O hv 6 62 63 CuPF6 NTs Ph TsN3 [TsN] + -N2 Ph o Ph 10 C PhI=NTs O 82-85 84

Both routes provide product with 41% ee NC Me 71 70 Ph

Ph 42 39-43

Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5889

12 Carreira Discovers a Nitro-Transfer Amination of Enols Me Me Me Me New class of L*Mn developed N N N Mn O O OTMS O (saltmen)Mn(N) H TFAA, pyridine N CF3 O -78o to 23oC 78% OMe OMe

(saltmen)Mn(N) OTMS O TFAA, pyridine H N CF3

-78o to 23oC O 69%

1. (saltmen)Mn(N) O O TFAA O OH O O Ph O 75% 2. SiO or H O+ Ph O N CF3 OTBS 2 3 H 7:1 selectivity OTBS

1. (saltmen)Mn(N) O O TFAA O OH O O Ph O 75% 2. SiO or H O+ Ph O N CF3 2 3 H 1:1 selectivity

All reactions involve stoichiometric imidotransfer to Requires electron-rich olefins

Du Bois, J.; Hong, J.; Carreira, E. M.; Day, M. W. J. Am. Chem. Soc. 1996, 116, 915 Du Bois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 3179

Recent Advances in Asymmetric Aziridination Me Me

Katsuki returns N N Mn O O - PF6 Move to ligand with less bulky substituents on diimide bridge proves critical, but Me R R Me

substrate scope is very limited R: (R)-(4-t-BuC6H4)(Et)CH A

A Ts Ph Ph N 61% ee Me Me PhI=NTs 9%

N N Mn O O B Ts Ph Ph Ph Ph N 94% ee PhI=NTs 76% AcO- B Asymmetric version of Carreira's reactant

N N N Mn O O Ph Ts Ph N R=i-Pr: 96% ee, 53% R=Me: 85% ee, 72% R TFAA R

Noda, L.; Hosoya, N.; Irie, R.; Ito, Y.; Katsuki, T. Synlett 1993 463 Nishikori, H.; Katsuki, T. Tetrahedron Lett. 1996, 37, 9246 Minakata, S.; Ando, T.; Nishimura, M.; Ryu, I. Komatsu, M. Angew. Chem. Int. Ed. 1998, 37, 3392

13 Ring-Opening of meso-Epoxides

Metal selection provides key lead H H N N Epoxidation transition state resembles the ground state structure of M coordinated epoxides t-Bu O O t-Bu

t-Bu t-Bu R' R' R R Nu- O O X X M * M * X X

Epoxidation Lewis Acid Catalysis Activation of Epoxides

Would require a (salen)M complex that favored epoxide coordination

Catalyst (2 mol%) N3 O + TMSN3 OTMS M %conv %ee

AlCl 73 5

TiCl2 74 7 CrCl 95 88

MnCl 12 2

CoI 22 48

Martinez, L. E.; Leighton, J. L; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897 Hansen, K. B.; Leighton, J. L.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 10924

Scope of Epoxide Ring-Opening Reactions H H Sensitive to local steric environment N N Cr t-Bu O ClO t-Bu RO RO N 1. Cat. (2 mol%), Et2O, rt 3 t-Bu t-Bu O + TMSN3 BnO 2. CSA, MeOH BnO OH RO RO R=TMS, TBDMS: no reaction, R=Bn: 98% ee, >95%

N3 1. Cat. (2 mol%), Et2O, rt X O + TMSN3 X 2. CSA, MeOH OH

Tolerant of a range of functionalities

Me N3 N3 N3 N3 N3 N3 O F3COCN O Me OH OH OH OH TBSO OH OH

82% ee 97% ee 95% ee 94% ee 96% ee 92% ee 65% 96% 87% 77% 95% 85%

Enantioselectivity decreases as ring size increases

N3 N3 N3 O OH OH OH 93% ee 85% ee 42% ee no reaction 97% 96% 99%

Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N.; J. Am. Chem. Soc. 1995, 117, 5897 Leighton, J. L.; Jacobsen, E. N. J. Org. Chem. 1996, 61, 7893 Martinez, L. E.; Nugent, W. A.; Jacobsen, E. N. J. Org. Chem. 1996, 61, 7963 Kassab, D. J.; Ganem, B. J. Org. Chem. 1999, 64, 1782

14 Epoxide Ring-Opening Reaction Kinetics and Implications H H N N3N Cr t-Bu O O t-Bu Reaction is second order with respect to catalyst t-Bu t-Bu

N 1. Cat. (2 mol%), Et2O, rt 3 O 2 -1 0 rate=k[Cat*N2] [epoxide] [HN3] OH

Two geometries can be envisioned for selectivity-determining step

t-Bu t-Bu N 3 t-Bu t-Bu N N O 3O Cr N N O Cr O N t-Bu t-Bu O t-Bu O t-Bu t-Bu t-Bu N3 N3

t-Bu N t-Bu N O O Cr N Cr N O O

t-Bu t-Bu t-Bu t-Bu

"head to head" "head to tail"

Hansen, K. B.; Leighton, J. L.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 10924

Dimeric Catalysts in Epoxide-Opening Reactions

Suggestive of geometry of enantiodetermining step H H N N3N Cr Attempts to develop a "head to head" catalyst t-Bu O O t-Bu

t-Bu t-Bu 2 n-Bu A N N

H H H H N N N N Cr Cr H H t-Bu O O t-Bu t-Bu O O t-Bu Cl Cl N N3N Cr t-Bu t-Bu t-Bu t-Bu t-Bu O O OAc

8% ee 90% ee t-Bu t-Bu B Attempts to develop a "head to tail" catalyst

Catalyst n %ee k (M-1min-1) H H H H A 93 0.6 N N3N O O N N3N B 94 1.2 Cr Cr C1 t-Bu O O O O O O t-Bu 2 90 15.7 n C2 4 90 15.1 C3 5 93 27.4 t-Bu t-Bu t-Bu t-Bu C4 6 93 15.8 C5 7 93 7.9 C1: n=2, C2: n=4, C3: n=5, C4: n=6, C5: n=7, C6: n=8, C7: n=10 C6 8 94 10.5 C7 10 92 4.4

Konsler, R. G.; Karl. J.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 10780

15 Resolution of Terminal Epoxides

Practical Application of the ARO H H N N3N 1. Cat., 0.5 eq. TMSN Cr O 3 OTMS t-Bu O O t-Bu Cl 97% ee Cl N3 76% (racemic) 2. 0.5 eq. TMSN3 t-Bu t-Bu

Reaction is general for terminal epoxides

OTMS OTMS OTMS OTMS OTMS N N3 N3 TMSO N3 Me 3 Et n-Bu O N3

97% ee, 97% 97%ee, 83% 97% ee, 89% 96% ee, 96% 93%ee, 74%

OTMS OTMS OTMS OTMS OTMS Ph N3 N3 N3 EtO N3 NC N3 OEt

93%ee, 94% 97% ee, 84% 98% ee, 94% 89% ee, 96% 92% ee, 80%

Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 7420

Conclusions

M(salen) system constitutes a privelidged class of catalsysts capable of participating in myriad of asymmetric reactions

Efforts in salen ligand catalysis were pioneering in the field of ligand controlled asymmetric catalysis

Enantioselectivity in M(salen) system is governed by a complicated interplay of electronic and steric variables

Future Research Considerations

Develop a more thorough understanding of the mechanistic pathway of M(salen) systems

Expand substrate scope: simple terminal olefins and trans-olefins remain a problem

Make aziridinations synthetically feasible for non-conjugated olefins

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