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Small Organic Molecule catalyzed asymmetric Mannich reactions T h e D i r e c t C a t a l y t i c A s y m m e t r i cT h r e e C o m p o n e n t M a n n i c h R e a c t i o nOD M S OO+L P r o l i n e3 5 m o l %r . t .H ROOD M S O+L P r o l i n e1 2 4 8 hC H O N H2O M e+1 2 h5 0 %N H P M P9 4 % e e3 5 m o l %p a n i s i d i n e ( 1 . 1 e q . )ON H P M PRR =N O2i P r i B u n B u y i e l d : 3 5 9 0 % 。e e : 7 3 9 6 %OD M S OO+L P r o l i n e3 5 m o l %r . t .C H O N H 2O M e+1 2 h5 0 %N H P M PR1R2R2R1a . R1= H , R2= M e , 9 9 % e e 。b . R1 = H , R2= O M e , 9 8 % e e , y i e l d 9 3 %R1= M e , R2= H , 9 4 % e e 。 t o t a l y i e l d 9 6 %B e n j a m i n L i s t . J . A m . C h e m . S o c . 2 0 0 0 , 1 2 2 ( 3 8 ) , 9 3 3 6 7The Direct and Enantioselective, OnePot, ThreeComponent, CrossMannich Reaction of Aldehydes Angew. Chem. Int. Ed. 2022, 42, 3677 –3680 Y. Hayashi,W. Tsuboi, I. Ashimine, T. Urushima,Dr. M. Shoji Department of Industrial Chemistry, Faculty of Engineering Tokyo University of Science, Kagurazaka Threeponent Mannich reaction with various acceptor aldehydes Nmethyl2pyrrolidinone (NMP) Threeponent Mannich reaction with various donor aldehydes. 4. Claisen Condensation ? General Scheme 2 R C H 2 C O 2 E tB :R C H 2 C C H C O 2 E tRO? Mechanism R C H C O E tOB :HR C H C O E tO+ R C H COHO E tR C H COHO E tR C H C O E tO E t OR C H2C C H C O2E tRO ? 一種酯的自身縮合 ? Scope of application ? 一種含 ?H 的酯與一種不含 ?H的酯之間的縮合 ? Examples NC O 2 E t + N a HNC O C H C O 2 E tE tE t C H 2 C O 2 E tC O 2 E tC O 2 E t+ P h C H 2 C O 2 E tE t O N aE t O HC O C H C O 2 E tP hC O 2 E t 1 7 5 o C C OC HP hC O 2 E tC O 2 E t? Directed Claisen condensation L D A R C H C O 2 E t R 39。 C O C l R C H C O 2 E tC O R 39。R C H 2 C O 2 E tC O 2 M eC O 2 M eNL iC O 2 M eO5. Dickmann Condensation ( C H 2 ) nC O 2 E tC O 2 E t B :( C H 2 ) n 1OC O 2 E t分 子 內(nèi) C l a i s e n 縮 合 反 應(yīng)Chapter 3 Formation of CarbonCarbon Doule Bonds 1. ?Elemination reactions （ ?消去反應(yīng) ） C CH XC C + H XX = O H , O C O R , 鹵 素 , O S O 2 A r , N + R 3 , S + R 2 e t a l .R e g i o s e l e c t i v i t yS a y t z e f f r u l eH o f m a n n r u l eX = O H , O C O R , 鹵 素 , O S O 2 A r ,X = N + R 3 , S + R 2S t e r e o s e l e c t i v i t yS y n e l i m i n a t i o nA n t i e l i m i n a t i o nH o f m a n n e l i m i n a t i o n sS a y t z e f f e l i m i n a t i o n sA n t i e l i m i n a t i o nI. The Synthetic Methods of Alklenes 2. Pyrolytic syn eliminations（順式熱消去反應(yīng) ） C CH OC C + R C O 2 HRO3 0 0 ~ 5 0 0 o CApplications: Synthesis of terminal alkenes from primary acetates Disadvantages: High reaction temperature C H 3 C H 2 C H 2 C H 2 O C O C H 3 5 0 0 o CN2C H 3 C H 2 C H = C H 2 1 0 0 %C CH OC C + H S C S RS RS1 0 0 ~ 2 0 0 o COCope reaction C CH N R 2C C + R 2 N O HO1 0 0 ~ 2 0 0 o CChugave reaction 反應(yīng)條件比對應(yīng)的酯熱消去溫和。 3. Wittig and related reactions （ Wittig 及有關(guān)反應(yīng)） ? Wittig Reaction G. Wittig received the 1979 Nobel Prize in Chemistry for many significant contributions to Organic Chemistry which included not only the Wittig reaction, but also PhLi prepared by metal halogen exchange, benzyne, and the Wittig rearrangement. COR 39。 ( H )R + C HR 39。R X + C CR 39。R RR 39。( H )P h 3 P? General Scheme ? Mild reaction conditions。 ? The position of the double bond is unambiguous. ? Features OM e M g I1 )2 ) H+H O M eC H 2P h 3 P = C H 2 H 2 OC H 3 C H 2+? Representative Examples Example 1 Example 2 Example 3 Example 4 ? Mechanism [2 + 2] cycloaddition. P h 3 P C H 2 C H 3 + E t C H O +D M F + L iC 6 H 6 + L iZ / E9 6 / 4 0 / 1 0 0P h C H = C H E t P h 3 P O? Influence of solvent on the selectivity ? Activity and stereoselectivity of Yild P h 3 P C H R R = a l k y l ， E D GR =R = E W Ga l k e n y l o r a l k y n y lS t e r e o s e l e c t i v i t yZ ( m a j o r )Z / E ( m i x t u r e )E ( m a j o r )S t a b i l i t yi n c r e a s e? Schl246。sser modification: allows the preparation of trans vs. cis olefins. Schl246。sser Angew. Chem., Int. Ed. Eng. 1966, 5, 126. ? Stabilized Ylides Stabilized ylides are solid。 stable to storage, not particularly sensitive to moisture, and can even be purified by chromatography. Because they are stabilized, they are much less reactive than alkyl ylides. They react well with aldehydes, but only slowly with ketones. The first step, involving the addition to the aldehyde, is slow and reversible with stabilized ylides. ? Influence of solvent on the selectivity ? Wadsworth–Horner–Emmons Reaction Horner Chem. Ber. 1958, 91, 61。