stereoselective allylation of imines
TRANSCRIPT
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Stereoselective Allylation ofImines
Joshua PierceResearch Topic Seminar
10-30-04
Josh Pierce @ Wipf Group 1 11/3/2004
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Topic Overview:
• Introduction• Imines: Why is C=N different?• Synthesis of Allylating Reagents• Applications to Natural Product Synthesis• Previous Wipf Group Methodology• Current Work
Josh Pierce @ Wipf Group 2 11/3/2004
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Why is allylation a useful process?
• High degree of stereoselectivity• Great variety of reactivity depending on the allylmetal
species used• New methods for synthesis of allylating species have
allowed for highly functionalized product formation• Products of allylation reactions are useful buliding blocks
for natural product synthesis
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B(OR)2Me
H
+O
R H R
OH
Me
+R
OH
Me
TiCl4CH2Cl2, -78 ° C
93:9, E:Z 6 945:95, E:Z 96 4
•Type I: reactions wherein the syn/anti ratio reflects the Z/E ratio of the startingallylmetal
Classification of Allylating Reagents
•Type II: reactions wherein the product is predominately syn independent of the allylmetal geometry
SnR3Me
H
+O
R H R
OH
Me
+ R
OH
Me
BF3-OEt2CH2Cl2, -78 ° C
100:0, E:Z 98 20:100, E:Z 99 1
•Type III: reactions wherein the product is predominately anti independent of theallylmetal geometry
[Cr]Me
H
+O
R H R
OH
Me
+ R
OH
Me
THF, rt
100:0, E:Z 0 1000:100, E:Z 0 100
Josh Pierce @ Wipf Group 4 11/3/2004
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Comparison between C=O and C=NO
R H
N
R H
R' N
R H
R'R''
C=X bond E: 173-181 143 XXX kcal.mol-1
Polarization (δ): + 0.51 + 0.33 + 0.54
Reduced electrophilicity of the C=N double bond
Often unstable and difficult to synthesize - most methodology has only been directed to aromatic imines
Side reactions observed with organometallics
E-Z geometery problem associated with C=N double bonds
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Allyllithium Reagents:
ClLi+ + NR3R1
R2Cl
R1
R2N
R
Li
NH
R
R
Very basic: Restricted to aromatic or α-substituted aldimines
Cannot be synthesized via halogen-metal exchange reaction due to the competingsubstitution process
Most commonly formed by the trasnmetalation of the corresponding allyltin species
Chloroallyllithium useful species for the synthesis of 2-vinyl aziridines:
J. Organomet. Chem. 1980, 202, 233.
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Allylmagnesium Reagents
MgX NR2H
R1R1 R1
NHR2 NHR2
+
Very low diastereoselectivity seen with crotylmagnesium bromide:
60 : 40
Higher yields seen that with allyllithium reagents; sometimes α-protons are tolerated in alaphatic aldimines (lower yield)
R1
MgX NR3H
R
R1 R2
NHR3
50-78% yield
Review: Kleinmann, E. F.; Volkmann, R. A. In Compreh. Org. Synth., Heathcock, C. H., Ed.; Pergamon: Oxford, 1990; Vol. 2, p 975.
Josh Pierce @ Wipf Group 7 11/3/2004
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Selectivity of Allylmagnesium
N
H
R
MgClPh Ph
NHRNHR
Ph
Cram anti-Cram
R = n-Pr 84 : 16 = i-Pr 70 : 30
+
N
H
i-Pr
O
HN
O
HN
O OMe OMe OMe
i-Pri-Pr
MgCl+
chelation non-chelation (Cram)79 : 21
J. Am. Chem. Soc. 1986,108, 7778.
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Addition of External Lewis AcidReverses Selectivity
Tetrahedron Lett. 1992, 33, 3355.
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Allylzinc ReagentsUsually prepared from the treatment of an allylhalide with zinc dust or zinc saltsunder Barbier condiditons - often chosen due to ease of preparation and compatibilitywith other organic functional groups
Diastereoselectivity of crotylzinc reagents low as with magnesium and lithium
Much more tolerant of alaphatic aldimines - High diastereoselectivity seenwhen chiral auxiliary is used in allylations:
Org. Lett 2001, 3, 3943.
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Masked Allylzincs
J. Org. Chem. 1999, 64, 186.
Synthesis of allylmetals has traditionally been plauged by Wurtz homocoupling products
Zinc allylations are reversible!
Creative Solution:
Josh Pierce @ Wipf Group 11 11/3/2004
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J. Org. Chem. 1999, 64, 186.
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Allylzinc reagents give low yield and almost no diastereoselectivity in theabove reaction
The use of allyl 9-BBN increased the selectivity to 98:2! (102 major)
Reversal of selectivity seen with methylallyl 9-BBN used (103 major)
Allylic Boron Reagents
J. Am. Chem. Soc. 1986, 108, 7778.
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Reagent of Choice for Cram Selectivity
Aldehyde ratio
Cram anti-Cram
J. Am. Chem. Soc. 1986, 108, 7778.
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Dimetallic Allylating Reagents:Indium
J. Org. Chem. 2003, 68, 1309.
Josh Pierce @ Wipf Group 15 11/3/2004
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Josh Pierce @ Wipf Group 16 11/3/2004
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Allylic ZirconiumMethods of formation were limited to reaction of Cp2ZrCl2 with ethersor hydrozirconation of allenes
J. Org. Chem. 2004, 69, 3302.
Josh Pierce @ Wipf Group 17 11/3/2004
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Addition to Imines
J. Org. Chem. 2004, 69, 3302
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Catalytic Asymmetric Allylation ofImines: Palladium
J. Am. Chem. Soc. 1998, 120, 4242.
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Proposed Catalytic Cycle
J. Am. Chem. Soc. 1998, 120, 4242.
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Why so much interest?Allylation reactions can be used to form similar intermediatesas thealdol reaction, one of the most used synthetic reactions.
The products of allylation reactions can be much more versatile - this hasbeen exploited for decades with aldehydes and ketones but due to lack ofgood methodology, the application of this to imine chemistry has fallen behindbut is constantly growing due to the large amount of nitrogen containing natural products and investigation into stereoselective imine chemistry.
Josh Pierce @ Wipf Group 21 11/3/2004
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Application to Natural Product Synthesis
Allylation first attempted with allylsilane and allylstannes with various lewis acids, but low yields and diastereoselectivities were obtained.
99% yield
J. Org. Chem. 2002, 67, 6361
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Practically and Scalability
77% yieldMulti-gram scale
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Narrow Range of Conditions
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1-O-β-D-Glucopyranosyl-5-deoxyadenophorine
Retrosynthetic Analysis:
J. Org. Chem. 2004, 69, 1497.
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Proposed Allylation TS:
Allylation preformed with allylmagnesiumbromide in 87% yield
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Synthesis of Cyclohexenylamines
J. Org. Chem. ASAP
Barbier allylation conditions have generally been restricted to simple allylating reagents,mainly allyl bromide. Also, most methodology has been accomplished with aromatic aldimines
Josh Pierce @ Wipf Group 27 11/3/2004
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Ring-Closing Methathesis
J. Org. Chem. ASAP
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Previous Work in the Wipf Group1.) Cp2ZrHCl2.) Me2Zn
MeZn C4H9
CH2I2C4H9
Zn C4H9I
NP(O)Ph2
R1MeZnC4H9
NHP(O)Ph2
PhC4H9
NHP(O)Ph2
PhC4H9
+
71%; 85:15
Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773.
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Josh Pierce @ Wipf Group 30 11/3/2004