steric and electronic controllers in ring-closing metathesis … · introduction – ring closing...
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Steric and Electronic Controllers in Ring-Closing Metathesis
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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)?
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%)
linalool citronellene
Pairwise competition experiments:~0.02M of each substrate4-10 mol% Grubbs catalyst*90-100 mol% Grubbs catalyst
Hoye, T.R.; Zhao, H. Org. Lett. 1999, I, 1123-1125
Sterics: Allylic Substitution
teubrevin G teubrevin H
Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492-4501
Sterics: Allylic Substitution
53%30-35 mol% A
>1 week!
Catalyst A =
Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492-4501
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
Sterics: Substituent Groups
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
Sterics: Substituent Groups
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%
Catalyst B = Catalyst A = Ar = 2,6-i-Pr2C6H3
Kirkland, T.A.; Grubbs, R.H. J. Org. Chem. 1997, 62, 7310-7318
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
Electronics: Allylic Substitution
>200x (100%)10x (60%)8x (60%)1.5x (50%)
linalool citronellene
Increasing Reactivity
Pairwise competition experiments:~0.02M of each substrate4-10 mol% Grubbs catalyst*90-100 mol% Grubbs catalyst
Hoye, T.R.; Zhao, H. Org. Lett. 1999, I, 1123-1125
Electronics: Allylic Substitution
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
Electronics: Allylic Substitution
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
Electronics: Allylic Substitution
Ackermann, L.; Tom, D.E.; Furstner, A. Tetrahedron 2000, 56, 2195-2202
Electronics: Allylic Substitution
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
Ackermann, L.; Tom, D.E.; Furstner, A. Tetrahedron 2000, 56, 2195-2202
R=2,4,6-trimethylphenylAr = 2,6-i-Pr2C6H3
Electronics: Allylic Substitution
30-35 mol% A
>3 days
Catalyst A = Catalyst B =
10 mol% B
34 h90%
R=2,4,6-trimethylphenyl
35%
Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492-4501
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)
Electronics: Alkene Substitution
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
Electronics: Alkene Substitution
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
Catalyst B = Catalyst A = Ar = 2,6-i-Pr2C6H3
Kirkland, T.A.; Grubbs, R.H. J. Org. Chem. 1997, 62, 7310-7318
Hydroxyl Group: Activating Effect
5x (80%)*
>200x (100%)10x (60%)
~25x (80%)*
8x (60%)1.5x (50%)
linalool citronellene
Pairwise competition experiments:~0.02M of each substrate4-10 mol% Grubbs catalyst*90-100 mol% Grubbs catalyst
Hoye, T.R.; Zhao, H. Org. Lett. 1999, I, 1123-1125
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
Hoye, T.R.; Zhao, H. Org. Lett. 1999, I, 1123-1125
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 =
Hoye, T.R.; Zhao, H. Org. Lett. 1999, I, 1123-1125
Hydroxyl Group: Mechanism
mol% A +
68% 20%
Catalyst A =
Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492-4501
Hydroxyl Group: Mechanism
Two Competing Mechanisms
Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492-4501
RCM
Undesired
RCM
Undesired
Hydroxyl Group: Catalyst Control
88%8 mol% B, ∆
Catalyst B =
R=2,4,6-trimethylphenyl
Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492-4501
Hydroxyl Group: Catalyst Control
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 =
R=2,4,6-trimethylphenyl
Fukuda, Y; Sasaki, H.; Shindo, M.; Shishido, K. Tetrahedron Lett. 2002, 43, 2047-2049
Hydroxyl Group: Catalyst Control
Catalyst Mol% Time (h) Yield (%)
A 5 2 0
B 20 20 0
C 1.5 2 69
Ackermann, L.; Tom, D.E.; Furstner, A. Tetrahedron 2000, 56, 2195-2202
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
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
Ackermann, L.; Tom, D.E.; Furstner, A. Tetrahedron 2000, 56, 2195-2202
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