steric and electronic controllers in ring-closing metathesis … · introduction – ring closing...

Steric and Electronic Controllers in Ring-Closing Metathesis

Reactions

Jennifer E. FarrugiaOctober 29, 2003

Steric and Electronic Controllers

How do substrate sterics affect the reactivity/ selectivity in ring-closing metathesis (RCM)?

How do substrate electronics affect the reactivity/selectivity in ring-closing metathesis (RCM)?

Outline

Introduction to RCMCatalystsRCM MechanismSteric ControllersElectronic ControllersConclusion

Introduction – Ring Closing Metathesis

Driven primarily by entropy gained by release of ethylene or other volatile side products

Very powerful method for the formation of unsaturated cyclic systems from acyclic dienes

Proceeds via a sequence of formal [2+2] cycloadditions/ cycloreversions

Ackermann, L.; Tom, D.E.; Furstner, A. Tetrahedron 2000, 56, 2195-2202

CatalystsMolybdenum alkylidene complex – Schrock

Superior reactivity even toward highly substituted alkenesStable for long periods in an inert atmosphereSensitive to oxygen and moisture as well as proticcompounds

Ruthenium alkylidene complex – Grubbs

Most widely used catalyst in organic synthesis for RCM and CM reactionsSomewhat less active, but significantly more stable, easier to handle, and shows excellent compatibility with functional groups

2nd generation ruthenium alkylidene complex

Allow the formation of tri- and tetra-substituted cycloalkenesMore robust than the original Grubbs carbene in solution as well as in the solid state

Ar = 2,6-i-Pr2C6H3

R=2,4,6-trimethylphenyl

Woo Lee, C.; Grubbs, R.H. J. Org. Chem. 2001, 66, 7155-7158Hoveyda, A.H.; Schrock, R.R. Chem. Eur. J. 2001, 7, 945-950

RCM Mechanism

-PCy3

2,4-configuration

-PCy3

-PCy3

2,3-configuration

-

PCy3

RCM Product

Ulman, M.; Grubbs, R.H. Organometallics 1998, 17, 2484-2489

Steric Controllers

Allylic substitution

Alkene substitution

Substrate branching

Tuning substituent groups

Conformational constraints

Sterics: Allylic Substitution

linalool citronellene

Hoye, T.R.; Zhao, H. Org. Lett. 1999, I, 1123-1125

Sterics: Allylic SubstitutionIncreasing Reactivity

5x (80%)* 8x (60%)1.5x (50%)

>200x (100%)


Pairwise competition experiments:~0.02M of each substrate4-10 mol% Grubbs catalyst*90-100 mol% Grubbs catalyst



teubrevin G teubrevin H

Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492-4501


53%30-35 mol% A

>1 week!

Catalyst A =


Sterics: Alkene Substitution

R RR R A: Yield = 93%

B: No RCM product

R RR R A: Yield = 61%

B: No RCM product

R = CO2Et

Catalyst B = Catalyst A = Ar = 2,6-i-Pr2C6H3

Kirkland, T.A.; Grubbs, R.H. J. Org. Chem. 1997, 62, 7310-7318

Sterics: Substrate Branching

RCM

1. NaH2. BuLi3. Substrate B,

THF, -78C

70%Callipeltoside A

A B

Hoye, T.R.; Zhao, H. Org. Lett. 1999, 1, 169-171

Sterics: Substituent Groups

Double RCM Strategy

One-Shot!a

b

c

d

ab/cd

ac/bd

fused bicycle

dumbell bicycle

C-N bond formation

C-C bond formation

Ma, S.; Ni, B. Org. Lett. 2002, 4, 639-641


5 mol% A

(R = Me) 23 h 64% (2 : 3 = 1 : 3.6)

(R = n-Pr) 14.5 h 41% (2 : 3 = 1 : 3.8)

(R = H) 2 h 88% (2 : 3 = 21 : 1)

Catalyst A =

Ma, S.; Ni, B. Org. Lett. 2002, 4, 639-641


89%

39%

Ma, S.; Ni, B. Org. Lett. 2002, 4, 639-641

+

23%

1 mol% A

30 min

5 mol% A

1 h

Catalyst A =

Sterics: Conformational Constraints

R RRR

A, B: No RCM product

X

R RR R

A, B: No RCM product

X

R R

R R

R R

A: Yield = 100%

B: Yield = 96%

R R

R = CO2EtA: Yield = 96%

B: Yield = 25%



Sterics: Conformational Constraints

5-7 mol% A

2h

73% Yield

(17% dimer)

5-7 mol% A

30 min

94% Yield

(only product)

Catalyst A =

Crimmins, M.T.; Choy, A.L. J. Org. Chem. 1997, 62, 7548-7549

Electronic Controllers

Allylic substitution

Alkene substitution

Electronics: Allylic Substitution

>200x (100%)10x (60%)8x (60%)1.5x (50%)


Increasing Reactivity




Fukuda, Y; Shindo, M.; Shishido, K. Org. Lett. 2003, 5, 749-751


1) 10 mol% A48h

2) Hydrolysis

R1 = Bn, TMS, MOM, Bz

R2 = Me, Et, Ph

R1 R2 Yield (%) dr

TMS Et 84 86:14

Catalyst A =

Fukuda, Y; Sasaki, H.; Shindo, M.; Shishido, K. Tetrahedron Lett. 2002, 43, 2047-2049


Yield (%) of 2 diastereomericR (recovered 1 (%)) ratioH 7 (81) 59:41Bz 95 (5) 72:28MOM 92 (5) 85:14Bn 94 (6) 88:12TMS quantitative (0) 87:13

1 2

10 mol% A48h

Catalyst A =

Fukuda, Y; Shindo, M.; Shishido, K. Org. Lett. 2003, 5, 749-751


Catalyst Mol% Time (h) Yield (%)

A 5 1 92

B 5 60 32

C 5 2 89

B 20 120! 77

C 1 5 71

Catalyst A B C


R=2,4,6-trimethylphenylAr = 2,6-i-Pr2C6H3


30-35 mol% A

>3 days

Catalyst A = Catalyst B =

10 mol% B

34 h90%


35%


Electronics: Alkene Substitution

Ma, S.; Ni, B. Org. Lett. 2002, 4, 639-641

a

b

c

d

ab/cd

ac/bd

fused bicycle

dumbell bicycle

Only

Product!5 mol% A

Catalyst A = (R1 = Me, R2 = H) 5 h 86% (R2 = H)

(R1 = H, R2 = Me) 23 h 43% (R2 = Me)


5 mol% A+

(R = H) 5 h, 77% 8.9 1

(R = Me) 23 h, 76% 20 1

5 mol% A+

Catalyst A = 2h, 88% 21 1

Ma, S., Ni, B. Org. Lett. 2002, 4, 639-641

Electronics: Alkene SubstitutionR

Catalyst A =

R k (1/min) Yield (%)

CH3O- 0.0062 85

CH3CO- 0.0154 83

PhSO2- 0.0178 86

HOCH2- 0.0215 77

EtOOC- 0.0261 65

H- 0.0762 80

5 mol% A

Basu, K.; Cabral, J.A.; Paquette, L.A. Tetrahedron Lett. 2002, 43, 5453-5456


R R

X

R R X

X Yield (%) with A Yield (%) with BPh 97 25

CO2Me 89 5

CH2OH decomp. 98

CH2OAc 100 97R = CO2Et



Allylic Hydroxyl Group Effects

Hydroxyl Activating Effect

Competing Mechanisms

Catalyst Control

Hydroxyl Group: Activating Effect

5x (80%)*

>200x (100%)10x (60%)

~25x (80%)*

8x (60%)1.5x (50%)




Hydroxyl Group: Activating Effect

Possible Explanations

•Rapid and reversible ligand exchange

•Alkoxy for chloride

•Alcohol for phosphine

•Hydrogen bonding between hydroxy group and one of the chloride ligands

Ru CHR'RO

Cl (PCy3)

(PCy3)

Ru CHR'

(ROH)

(PCy3)

ClCl


Hydroxyl Group: Allylic Substitution

1592U89-potent inhibitor of HIV reverse transcriptase

Crimmins, M.T.; King, B.W.; J. Org. Chem. 1996, 61, 4192-4193

Hydroxyl Group: Allylic Substitution

1 mol% A,

30 min 97%

LiBH4

THF, MeOH

Catalyst A =

Crimmins, M.T.; King, B.W.; J. Org. Chem. 1996, 61, 4192-4193

Hydroxyl Group: Mechanism

150 mol% A+

1 : 1.5

RCM Undesired

Catalyst A =



~50 mol % A

Catalyst A =

Hoye, T.R.; Zhao, H. Org. Lett. 1999, 1, 169-171


mol% A +

68% 20%

Catalyst A =



Two Competing Mechanisms


RCM

Undesired

RCM

Undesired

Hydroxyl Group: Catalyst Control

88%8 mol% B, ∆

Catalyst B =




HO 5 mol% B, 1h

• R = Me, Et, and Ph gave the desired RCM products in 78, 75, and 92% yield. However, no diastereoselectivity was observed.

Catalyst B =


Fukuda, Y; Sasaki, H.; Shindo, M.; Shishido, K. Tetrahedron Lett. 2002, 43, 2047-2049


Catalyst Mol% Time (h) Yield (%)

A 5 2 0

B 20 20 0

C 1.5 2 69


Catalyst A B C R=2,4,6-trimethylphenyl

Cat. BCat. C

29%69%

Conclusion: Steric Controllers

Allylic substitution: How?Fully substituted allylic centers Steric bulk (ie OTES)

Alkene substitution: How?Less substituted alkenes

Substrate branching: How?Additional substrate branching

Tuning Substituent Groups: How?Introduction of an alkyl group

Conformational constraints: How?The lack of conformational constraints

Conclusion: Electronic Controllers

Allylic substitution: How?Alkyl-substituted olefins bearing electron-withdrawing substituents

Alkene substitution: How?Electron-donating groups Electron-withdrawing groups

Conclusion: Allylic Hydroxyl Group

Hydroxyl Activating Effect: How?Allylic hydroxyl groups greatly accelerate the rate

Competing Mechanisms: How?Two competing mechanisms have been proposed

Catalyst Control: How?Schrock’s molybdenum catalyst The second generation Grubbs ruthenium complex

Thank You

Dr. James JacksonDr. Simona MarinceanDr. Mischa RedkoRobert GentnerTulika DattaEric Bassett

Dr. Dennis MillerDr. Navine AsthanaMike ShaferLars Peereboom

Questions?

Background

Olefin metathesis was first observed in the 1950’s by industrialchemists

In 1967, Nissim Calderon figured out that the unexpected products were due to cleavage and reformation of the olefins’ double bonds

In 1971, Yves Chauvin and Jean-Louis Herisson proposed a mechanism, which turned out to be correct

Many people credit Grubbs ruthenium carbene catalyst and Schrocks molybdenum alkylidene with putting olefin metathesis in the forefront of organic synthesis

Schrock, R.R. Tetrahedron 1999, 55, 8141-8153Trnka, T.M.; Grubbs, R.H. Acc. Chem. Res. 2002, 34, 18-29

Advantages and Applications of RCM

Provides an elegant pathway for the formation of small, medium, and large-ring carbo- and heterocycles

Instrumental in natural product syntheses, including those of aspidosperma indole and bicyclic izidine alkaloids, as well as Callipeltoside A and conduritol derivatives

Aids in the synthesis of optically pure materials

Used in synthesis of carbocyclic nucleosides for the development of new antitumor and antiviral therapeutic agents

Hoveyda, A.H., Schrock, R.R. Chem. Eur. J. 2001, 7, 945-950

-PCy3

-PCy3

2,3-configuration

2,4-configuration

-PCy3

-PCy3

2,3-configuration

-PCy3

PCy3

-RCM

Product



RCM

Catalyst =

Royer, F.; Vilain, C.; Laurent, E.; Grimaud, L.; Org. Lett. 2003, 5, 2007-2009

steric and electronic controllers in ring-closing metathesis … · introduction – ring closing...

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