Stereoselective Allylation of Imines Joshua Pierce esearch Topic Seminar 10-30-04 Josh Pierce @ Wipf Group 1 11/3/2004
Topic Overview: Introduction Imines: Why is C=N different? Synthesis of Allylating eagents Applications to Natural Product Synthesis Previous Wipf Group Methodology Current Work Josh Pierce @ Wipf Group 2 11/3/2004
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 Josh Pierce @ Wipf Group 3 11/3/2004
Classification of Allylating eagents Type I: reactions wherein the syn/anti ratio reflects the Z/E ratio of the starting allylmetal Me H B(O) 2 + O H TiCl 4 CH 2 Cl 2, -78 C 93:9, E:Z 6 94 5:95, E:Z 96 4 OH Me + OH Me Type II: reactions wherein the product is predominately syn independent of the allylmetal geometry Me H Sn 3 + O H BF 3 -OEt 2 CH 2 Cl 2, -78 C 100:0, E:Z 98 2 0:100, E:Z 99 1 Type III: reactions wherein the product is predominately anti independent of the allylmetal geometry Me H [Cr] + O H THF, rt 100:0, E:Z 0 100 0:100, E:Z 0 100 OH OH Me Me + + OH OH Me Me Josh Pierce @ Wipf Group 4 11/3/2004
Comparison between C=O and C=N O N ' '' N ' H H H C=X bond E: 173-181 143 XXX kcal.mol -1 Polarization (δ): + 0.51 + 0.33 + 0.54 educed 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 Josh Pierce @ Wipf Group 5 11/3/2004
Allyllithium eagents: Very basic: estricted to aromatic or α-substituted aldimines Cannot be synthesized via halogen-metal exchange reaction due to the competing substitution process Most commonly formed by the trasnmetalation of the corresponding allyltin species Chloroallyllithium useful species for the synthesis of 2-vinyl aziridines: 1 Li + + N3 Cl 2 Li N 1 2 Cl N H J. Organomet. Chem. 1980, 202, 233. Josh Pierce @ Wipf Group 6 11/3/2004
Allylmagnesium eagents Higher yields seen that with allyllithium reagents; sometimes α-protons are tolerated in alaphatic aldimines (lower yield) 1 H MgX N 3 1 2 NH 3 50-78% yield Very low diastereoselectivity seen with crotylmagnesium bromide: MgX + NH 2 NH 2 H N 2 1 1 1 60 : 40 eview: Kleinmann, E. F.; Volkmann,. A. In Compreh. Org. Synth., Heathcock, C. H., Ed.; Pergamon: Oxford, 1990; Vol. 2, p 975. Josh Pierce @ Wipf Group 7 11/3/2004
Selectivity of Allylmagnesium Ph N H MgCl Ph NH Cram + Ph NH anti-cram = n-pr 84 : 16 = i-pr 70 : 30 O OMe O OMe O OMe MgCl H + N HN HN i-pr i-pr i-pr chelation non-chelation (Cram) 79 : 21 J. Am. Chem. Soc. 1986,108, 7778. Josh Pierce @ Wipf Group 8 11/3/2004
Addition of External Lewis Acid everses Selectivity Tetrahedron Lett. 1992, 33, 3355. Josh Pierce @ Wipf Group 9 11/3/2004
Allylzinc eagents Usually prepared from the treatment of an allylhalide with zinc dust or zinc salts under Barbier condiditons - often chosen due to ease of preparation and compatibility with other organic functional groups Diastereoselectivity of crotylzinc reagents low as with magnesium and lithium Much more tolerant of alaphatic aldimines - High diastereoselectivity seen when chiral auxiliary is used in allylations: Org. Lett 2001, 3, 3943. Josh Pierce @ Wipf Group 10 11/3/2004
Masked Allylzincs Synthesis of allylmetals has traditionally been plauged by Wurtz homocoupling products Creative Solution: Zinc allylations are reversible! J. Org. Chem. 1999, 64, 186. Josh Pierce @ Wipf Group 11 11/3/2004
J. Org. Chem. 1999, 64, 186. Josh Pierce @ Wipf Group 12 11/3/2004
Allylic Boron eagents Allylzinc reagents give low yield and almost no diastereoselectivity in the above reaction The use of allyl 9-BBN increased the selectivity to 98:2! (102 major) eversal of selectivity seen with methylallyl 9-BBN used (103 major) J. Am. Chem. Soc. 1986, 108, 7778. Josh Pierce @ Wipf Group 13 11/3/2004
eagent of Choice for Cram Selectivity Cram anti-cram Aldehyde ratio J. Am. Chem. Soc. 1986, 108, 7778. Josh Pierce @ Wipf Group 14 11/3/2004
Dimetallic Allylating eagents: Indium J. Org. Chem. 2003, 68, 1309. Josh Pierce @ Wipf Group 15 11/3/2004
Josh Pierce @ Wipf Group 16 11/3/2004
Allylic Zirconium Methods of formation were limited to reaction of Cp 2 ZrCl 2 with ethers or hydrozirconation of allenes J. Org. Chem. 2004, 69, 3302. Josh Pierce @ Wipf Group 17 11/3/2004
Addition to Imines J. Org. Chem. 2004, 69, 3302 Josh Pierce @ Wipf Group 18 11/3/2004
Catalytic Asymmetric Allylation of Imines: Palladium J. Am. Chem. Soc. 1998, 120, 4242. Josh Pierce @ Wipf Group 19 11/3/2004
Proposed Catalytic Cycle J. Am. Chem. Soc. 1998, 120, 4242. Josh Pierce @ Wipf Group 20 11/3/2004
Why so much interest? Allylation reactions can be used to form similar intermediatesas the aldol reaction, one of the most used synthetic reactions. The products of allylation reactions can be much more versatile - this has been exploited for decades with aldehydes and ketones but due to lack of good methodology, the application of this to imine chemistry has fallen behind but 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
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 Josh Pierce @ Wipf Group 22 11/3/2004
Practically and Scalability 77% yield Multi-gram scale Josh Pierce @ Wipf Group 23 11/3/2004
Narrow ange of Conditions Josh Pierce @ Wipf Group 24 11/3/2004
1-O-β-D-Glucopyranosyl-5- deoxyadenophorine etrosynthetic Analysis: J. Org. Chem. 2004, 69, 1497. Josh Pierce @ Wipf Group 25 11/3/2004
Proposed Allylation TS: Allylation preformed with allylmagnesium bromide in 87% yield Josh Pierce @ Wipf Group 26 11/3/2004
Synthesis of Cyclohexenylamines Barbier allylation conditions have generally been restricted to simple allylating reagents, mainly allyl bromide. Also, most methodology has been accomplished with aromatic aldimines J. Org. Chem. ASAP Josh Pierce @ Wipf Group 27 11/3/2004
ing-closing Methathesis J. Org. Chem. ASAP Josh Pierce @ Wipf Group 28 11/3/2004
Previous Work in the Wipf Group C 4 H 9 1.) Cp 2 ZrHCl 2.) Me 2 Zn MeZn C 4 H 9 CH 2 I 2 I Zn C 4 H 9 MeZn P(O)Ph 2 N 1 C 4 H 9 Ph NHP(O)Ph 2 + Ph C 4 H 9 71%; 85:15 NHP(O)Ph 2 C 4 H 9 Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773. Josh Pierce @ Wipf Group 29 11/3/2004
Josh Pierce @ Wipf Group 30 11/3/2004