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1 The Heck reaction R1 X + cat. PdX2 R2 R3N [R33P] R1 = Ar, ArCH2, X = Br, I, OTf R1 R2 • The Heck reaction is a versatile method for the coupling sp2 hybridised centres • Again it is not the purpose of this course to teach organometallics etc Br R3NH Br L Pd L oxidative addition R3N H L L Pd Br L +L H L Pd Br Pd Br Pd(0) (14e) Pd(II) (16e) L Pd(II) (16e) –L L Pd(II) (16e) Pd Br H syn addition β-hydride elimination Br Pd L 123.702 Organic Chemistry 2 Alkene isomerisation 0.01% Pd(OAc)2 R3N + O I L Pd I δ+ O δ– O 100°C syn addition Pd(I)Ln H H O β-hydride elimination Ph O L I Pd H hydropalladation Ph H O Pd(I)Ln H H Ph Ph O O O H Pd L I H Ph H Pd(I)Ln O L Pd I H • β-Hydride elimination is reversible • This alkenes can ‘walk’ or migrate to give the most stable alkene • Only restriction is every step must be syn 123.702 Organic Chemistry 3 Enantioselective Heck reaction Pd(dba)2 (3%), lig (6%) i-Pr2NEt + O O O TfO PPh2 N 92% >99% ee t-Bu lig amino acid derivative • With the use of chiral ligands the Heck reaction can be enantioselective • Intramolecular variant allows the construction of ring systems • The silver salt accelerates the reaction and prevents alkene isomerisation TBSO TBSO Pd[(R)-BINAP]Cl2 AgPO4, CaCO3 I N Me O H 78% 82% ee O N O I O O Pd2(dba)3 (R)-BINAP Me Ag3PO4 N,N-dimethylaniline PPh2 Me PPh2 N (R)-BINAP O O 71% ee 123.702 Organic Chemistry 4 Enantioselective Heck reaction in total synthesis OMe Me OTf Pd2(dba)3, (S)-BINAP, PMP, tol, 110°C O LnPd Me 82% 68%ee O OMe OMe O O OMe OMe Me i. H2, Pd/C ii. CAN O Me O O O xestoquinone O OMe O • (+)-Xestoquinone was isolated from the Pacific sponge Xestospongia sapra (not • • • shown!) and is a potent irreversible inhibitor of both the oncogenic protein tyrosine kinase pp60V-src encoded by the Rous sarcoma virus & the human epidermal growth factor kinase (EGF) The first total synthesis involved two Heck reactions; the first is enantioselective to give a quaternary centre and the second gives a second 6-ring Shawn P. Maddaford, Neil G. Andersen, Walter A. Cristofoli & Brian A. Keay, J. Am. Chem. Soc. 1996, 118, 10766 Review of asymmetric Heck: Chem. Rev. 2003, 103, 2945 123.702 Organic Chemistry 5 Suzuki-Miyuara reaction L Pd0 L –L R2 reductive elimination L Pd0 oxidative addition X R2 R1 L Pd X R1 L Pd R2 R2 transmetallation R1 B(OH)2 • The Suzuki-Miyuara reaction is (normally) the palladium catalysed coupling of an • • alkenyl or aryl halide with an alkenyl or aryl boronic acid Normally the components should be sp2 hybridised to avoid β-eliminations Mechanism etc is (surprise surprise) outside the scope of this course but the wonderful enantioselective examples are not... 123.702 Organic Chemistry 6 Enantioselective biaryl formation Me O B (PdClC3H5)2 lig1 CsF + Me Me O Me I PPh2 NMe2 Fe H Me lig1 60% 85% ee Br P(O)(OMe)2 + Pd2(dba)3 (0.2%) lig2 Me Me NMe2 P(O)(OMe)2 PCy2 B(OH)2 95% 86% ee lig2 • Virtually every (if not every...) reaction we have covered in this course has formed a • • stereogenic centre (central chirality) These two examples form axially chiral compounds Please note: both ligands are thought to be mono-dentate (in the active species at least, although they may be bidentate in ‘resting state’) via the phosphine 123.702 Organic Chemistry 7 Enantioselective Pd catalysed allylic substitution Ln+1Pd0 nuc.... X nuc • Displacement of good leaving group (OAc, OCO2R, halide, epoxide etc.) • Normally by soft nucleophile • Not direct displacement but via a palladium η3 complex LnPd0 X oxidative addition X σ-bond species and πallyl complex in equilibrium need vacant coordination site 0 Ln+1Pd Ln 0 LnPd PdII nuc X L nuc nuc Pd0Ln PdII X L electron deficient (cation) electrophile 123.702 Organic Chemistry 8 Regio- and stereoselectivity Me Me Pd(PPh3)4 Me Me MeO2C CO2Me Me Me Na SO2Ph Me L Me Me Pd L MeO2C H CO2Me • Palladium initially adds to the opposite face to the leaving group • • (although possible equilibrium) Soft nucleophiles (large, diffuse charge) usually attack from opposite face to PdLn Normally the nucleophile will add to the least hindered end of the allyl system (although ligand can can this) OAc Me Pd(PPh3)4 Me Me CO2Me Me Me Na Me Me MeO2C L Me Pd L H MeO2C Me CO2Me 123.702 Organic Chemistry 9 Enantioselectivity R R nuc Pd L L • Problem with inducing selectivity is that ligand is on opposite side to nucleophile • Bulky ligands can overcome this problem • Stereogenic centre can either be on: Substrate MeO2C + CO2Me Na OAc O Pd(0), cat. O CO2Me 81% 98%ee NH CO2Me HN PPh2 Ph2P Nucleophile O OAc + O Me Pd(0), cat. base 92% 75%ee O O Me O Me Fe N PPh2 Me PPh2 O N O O N Me 123.702 Organic Chemistry 10 Allylic substitution in total synthesis O O O NHTs O cat. (7.5mol%) Pd2dba3 (2.5mol%) Et3N NHTs N O N Ts 95% 97%ee meso OH H OTBS NTs O ROM– RCM OH N Ts H OH OTBS (–)-swainsonine O O NH HN PPh2 Ph2P • (–)-Swainsonine can be isolated from locoweeds; in cattle it causes symptons similar to mad cow disease (BSE) - hence plants named after the Spanish for crazy • In humans it shows anticancer, antiviral, and immunoregulatory properties • This synthesis is by Nicole Buschmann, Anke Rückert and Siegfried Blechert J. Org. • Chem. 2002, 67, 4325 The desymmetrisation is by Barry M. Trost and Daniel E. Patterson J. Org. Chem. 1998, 63, 1339 123.702 Organic Chemistry 11 Other catalytic enantioselective reactions • There are now a huge number of enantioselective reactions with more being invented / developed all the time • It is highly unlikely that this research in this vast, fascinating field will slow in the foreseeable future...(well I hope not anyway) • It should be possible to develop enantioselective variants of most reactions - even those that do not initially look set-up for such chemistry... • Below is an example of a chiral variant of the Schrock metathesis catalyst • The reaction involves desymmetrisation by selective reaction if one disubstituted alkene O O L2 (10mol%), PhH, 22°C, 48h N Me N i-Pr i-Pr Ar Me Me Me 91% 98% ee N O Mo THF Me O Ar Ph Me L2 123.702 Organic Chemistry 12 Summary of methods for stereoselective synthesis Method Advantages Disadvantages resolution both enantiomers available maximum 50% yield synthesis of (–)-propranolol chiral pool 100% ee guaranteed synthesis of (R)-sulcatol often only 1 enantiomer available Examples chiral auxiliary often excellent ee’s; built in extra steps to introduce resolving agent and remove auxiliary oxazolidinones chiral reagent alpine-borane®, Brown allylation reagents often excellent ee’s; stereoselectivity can be independent of substrate control chiral catalyst economical; only small amounts of recyclable material used only a few reagents are successful and often only for a few substrates only a few reactions are asymmetric hydrogenation; really successful; frequently Sharpless epoxidation a lack of substrate generality • Hopefully this course has shown that the area of stereoselective synthesis (or more particularly, methodology for stereoselective synthesis) is a vast & fascinating topic • There are many reactions we have not covered (there is already far too much material in the course) • I hope you found the course as interesting as I did... 123.702 Organic Chemistry