Chemistry of the Double Bond
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1 Chemistry of the Double ond. eactions of the Carbonyl Group. At Carbonyl.. eduction (hydride addition)..2 kylation..3 lylation/propargylation.2 At α-center (Enolate Chemistry).2. kylation.2.2 dol eaction.3 At β-carbon of Enone.3. Michael (,4-) Addition 2. eactions of lefins 2. xidation 2.. Epoxidation 2..2 Dihydroxylation 2..3 Aminohydroxylation 2.2 eduction Creation of Stereocenters sp 2 sp 3 Enantiofacial differentiation Y X 2 X 2 mirror prochiral sp 2 center X Y 2 si re anson J. Am. Chem. Soc. 966, 88, 273. Tetrahedron 974, 30, 3649.
2 Carbonyl Group Addition eactions eduction - A A - C-C bond formation A Difference between A and determines A.I. If steric, useful only if difference large: > > > > C 3 > Electronic effects may play a significant role - these are not yet fully understood! Addition to Carbonyl Group C u - u M S L M L S L M Cram Karabatsos Felkin-Anh l give the same result! Karabatsos and Felkin-Anh consistent with ground state or TS arguments. S
3 Chemistry of the carbonyl group: ürgi-dunitz angle Electrostatic repulsion between the nucleophile and the carbonyl filled π orbital... u...causes the nucleophile to attack at obtuse angle the ürgi-dunitz angle! u 07 C C π C= π C= Chemistry of the carbonyl group: reactivity boosted by Lewis acids Electrostatic repulsion between the nucleophile and the carbonyl filled π orbital... u... is eased if the oxygen can donate electrons to a powerful electrophile i.e., a strong Lewis acid u sp 2 oxygen C C two lone pairs π π C= C= F F F Lewis acid F 3
4 ydride educing Agents dehyde Ketone Acid chloride Lactone Epoxide Ester Acid Acid salt tert-amide itrile itro lefin Complete reduction in h eduction takes place in inert solvent nly partial reduction in h Insignificant reduciton in h a4 in Et 2 (t-u) (4) Sia2 in TF 7 9- in TF 8 3 in TF 9 ()3 in TF 0 4 in TF rown,.c. Chem. Engng. ews March 5, 979, 24. Enantioselective eduction - eviews Asymmetric Synthesis, vol. 2 (Morrison, J.D., Ed.) Chapter 2 eductions with Chiral oron educing Agents M.M. Midland Chapter 3 eductions with Chiral Modifications of thium uminium ydride E.. Grandbois, S.I. oward and J.D. Morrison Chapter 4 eductions with Chiral Dihydropyridine eagents Y. Inouye, J. da and. aba A Critical Examination of the elative Effectiveness of Various educing Agents for the Asymmetric eduction of Different Classes of Ketones.C. rown et al. J. rg. Chem. 987, 52, Asymmetric eductions with rganoborane eagents M.M. Midland Chem. ev. 989, 89, 553.
5 Enantioselective eductions - Darvon 4, Darvon > 95 % yield > 98 %ee Asteriscanolide 2 Darvon Cohen JC 980, 45, 582. P.A. Wender J. Am. Chem. Soc. 988, 0, Enantioselective eductions - Darvon Si 3 ) 4, Darvon 2) a, PMr MP Si 3 quant yield > 98 %ee (+)-Sterepolide 2 Darvon Cohen JC 980, 45, 582..M. Trost Angew. Chem., Int. Ed. Engl. 989, 28, 502.
6 ydride eduction - Chiral Auxiliaries n pine borane M.M. Midland JC 984, 49, 36. Eapine borane.c. rown JC 990, 55, Prapine borane.c.rown JC 990, 55,6328. Eapine hydride.c. rown TAS 990,, Enantride M.M. Midland JC 99, 56, 068. Cl 2 2 Et.C. rown JC 985, 50, JC 986, 5, S. Masamune JACS 986, 08, 7402, S. Itsuno JC 984, 49, oyori JACS 984, 06, S K.. Sharpless JC 984, 49, 386. E.J. Corey JACS 987, 09, E.J. Corey TL 989, 30, T. Mukaiyama Chem. Lett. 984, 207. Catalytic CS eduction C 2 Et 25 mol-% 65 mol-% 3. TF 94 % yield 93 %ee C 2 Et Ac Forskolin Corey, E.J.; da Silva Jardine, P. Tetrahedron Lett. 989, 30, 7297.
7 Catalytic CS eduction Cl 0 mol-% 60 mol-% 3. TF Cl. Cl CF 3 99 % yield 94 %ee Fluoxetine hydrochloride Prozac (Eli lly) Corey, E.J.; da Silva Jardine, P. Tetrahedron Lett. 989, 30, Catalytic CS eduction L S 2 -catecholborane D. 3 TF 60 mol-% 50 mol-% 0 mol-% cat (=,) L S 30 mol-% cat (=u) -26 ºC, 3.5 h 2 examples %ee 6 examples %ee p p p = β-naphthyl Catalyst Corey, E.J.; nk, J.. Tetrahedron Lett. 989, 30, 6275.
8 xazaborolidine eduction: ationalization 3. TF 3 2 S L S L 2 S L L n 3. TF 2 S L Asymmetric eduction: IAL- Et Et (S)- IAL- ()- IAL- X 300 mol-% (S)-IAL- TF X X r I (n-u) 3 Sn % yield % ee >95 >95 > X (S)-IAL- TF X c-c 6 c-c 6 C 2 n-uc() 2 C 2 % ee % yield
9 Asymmetric eduction: IAL- Et Et (S)- IAL- ()- IAL- 300 mol-% (S)-IAL- TF 87 % yield, 84 % ee (with methoxy-ial-) 00 mol-% (S)-IAL- TF 65 % yield 94 %ee IAL-: Transition State Model Et Et (S)- IAL- ()- IAL- S ' S ' favored unfavored because of binaphthyl/' repulsion
10 IAL-: Enantioface Differentiation Et Et (S)- IAL- ()- IAL- π Un S Un ' ' favored unfavored Effect of thyl Group on the Enantioselectivity in IAL- eduction n-alkyl (S)-IAL- S 95 %ee %ee (S)-IAL- S 79 9 (S)-IAL- S (S)-IAL- in 24 %ee!!! oyori,.; Tomino, I.; Yamada, M.; ishizawa, M. J. Am. Chem. Soc. 984, 06, 677.
11 Kinetic Discrimination in IAL- eduction of a Prostaglandin Intermediate C 2 IAL- 9 C 2 TS TS TS TS rel rate 9α:9β ()-IAL- >30 99: (S)-IAL- 95:5 Suzuki, M.; Yanagisawa, A.; oyori,. J. Am. Chem. Soc. 988, 0, 478. ITEAL AI C 2 C 2 Ac Ac C 2 Chelation controls selectivity (Saksena, A.K.; Mangiaracina, P. Tetrahedron Lett. 983, 24, 273.) Turnbull, M.D. et al. Tetrahedron Lett. 984, 25, 5449.
12 Stereocontrolled eduction PM Ac a(ac) 3 PM Ac PM PM Ac, C, rt PM PM PM PM Ac Ac MP Ac Saksena Tetrahedron Lett. 983, 24, 273. Turnbull Tetrahedron Lett. 984, 25, Evans, D.A. J. Am. Chem. Soc. 988, 0, Prestwich J. Am. Chem. Soc. 99, 3, ITEAL AI via 4(Ac)3 82 % TIPS diastereoselection 9: C Ac Ac TIPS - Et2, a4 82 % TIPS diastereoselection 2: Et C Et axial attack Evans, D.A. et al J. rg. Chem. 99, 56, 76.
13 Stereoselective eduction a L-selectride 0 3.TF Zh 4 ) 2 a 3 C a 4 /CeCl 3 a 3 C/CeCl a(ac) 3 /CeCl 3 2 Kishi, Y. J. Am. Chem. Soc. 99, 3, IAP-u Ketone eduction ()-IAP-u (S)-IAP-u Y C 2, X=Cl, r, I Y C 2, X=Cl, r, I Y C Y ()-IAP-u Y (S)-IAP-u Y C C 2, X=Cl, r, I C C 2, X=Cl, r, I C C Y = heteroatom, C = sp 2 or achiral sp 3 carbon epresentative ketones 2 96 %ee 98 %ee r 92 %ee SEt 93 %ee 92 %ee C %ee %ee 92 %ee oyori, Chem. Soc. ev. 989, 8, 87.
14 Catalytic Asymmetric eduction 98.2 % 30 g 9.7 mg catalyst.2 mg en 4 mg K 4 atm ml ipr 29.4 g ucl 2.(P 3 ) 3 catalyst to substrate ratio: : 5000 Asymmetric version: IAP and %ee Catalytic Asymmetric eduction 2.2 mg cat 2 (45 atm) ipr, 30 o C, 48h 00% conversion 80 %ee cat= Tol 2 P P Tol 2 Cl u Cl 2 2 T >,000,000 similar catalyst, 99 %ee, T > 00,000 oyori,. Angew. Chem,., Int. Ed. Engl. 988, 37, 703.
15 Carbonyl eduction eactions pine borane nc 5 nc K + ) n-u KAPA nc 5 2) C 2 3) 2 - ndlar nc 5 Midland, M.M. Tetrahedron Lett. 984, 40, 37. Carbonyl eduction eactions 2 C ) ().Cl Et 3, pyp 8% 2) I, Ag 2 88 % C=C 89% K-selectride -00 ºC 72 % via M M D'Aniello, F.; Mann, A.; Taddei, M. J. rg. Chem. 996, 6, Takahashi, T. et al. Tetrahedron Lett. 985, 26, 4463, 539.
16 Carbonyl addition reactions MgI * K Et 2 / 86 % Atrolactic acid 69 % ee Dauben, W.G.; Prelog, V. elv. Chim. Acta 953, 36, 325. 'Mgr ' % ee Whitesell, J.K. Chem. Commun. 982, 888. Chem. Commun. 983, 802. Carbonyl Addition eactions Si 3-23 o C Si 3 92 %ee Mukaiyama, T. J. Am. Chem. Soc. 979, 0, 455.
17 Asymmetric Carbonyl kylation C + Et 2 Zn rown,.c. Tetrahedron Lett. 989, 30, 555. C cat yield (%) config (% ee) (C 2 C 2 ) 4-C 6 4 PC=C C 5 C (86) (98) S (92) (92) S (82) S (94) (99) (99) S (75) Tf Tf hno, M. Tetrahedron Lett. 989, 30, Tanaka, K. Chem. Commun. 989, 700. kylation (C + Et 2 Zn) Tf Tf hno, M. Tetrahedron Lett. 989, 30, % ee (S) Tanaka, K. Tetrahedron Lett. 989, 30, % ee () Tanaka, K. Tetrahedron Lett. 989, 30, % ee (S) Tanaka, K. Tetrahedron Lett. 989, 30, % ee () Tanaka, K. Tetrahedron Lett. 989, 30, % ee () rown,.c. Tetrahedron Lett. 989, 30, % ee () Soai, K. J. Am. Chem. Soc. 987, 09, % ee (S) 2 oyori,. J. Am. Chem. Soc. 989,, % ee (S) Corey, E.J. Tetrahedron Lett. 987, 28, % ee (S)
18 lylation (C) Tol 2 S r S 2 Tol S 2 Corey JACS 989,, %ee () offmann,.w. er 98, 4, 375. eetz, M. Chem. & Ind. 988, 663. Pr i 2 C Pr i 2 C TMS 2 oush, W.. JACS 985, 07, %ee (S) Masamune, S. JC 987, 52, %ee (S) Masamune, S. JACS 989,, %ee rown,.c. JACS 983, 05, %ee eagent Control in Double Stereodifferentiation C eagent C + C lyl-mgcl 55. % 44.9 % Ti,-reagent S,S-reagent 98. % 0.5 %.9 % 99.5 %,-reagent Duthaler,.. et al. J. Am. Chem. Soc. 992, 4, 232.
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