D. A. Evans Introduction to Complex Aldol Bond Constructions Chem 206 Synthesis of Polyketide chains The Lonomycin Synthesis: An example of polypropionate assembage Evans, Ratz, Huff, Sheppard JACS 1995, 117, 3448 Given a polyprpionate chain of Iterating Me& OH substitutents select a disconnection point subunits of comparable complexity by adding C=o as illustrated R Meme m MeMeMeMeMe Me OMe OHOH HO 1 Focusing on the=O FG, there are 2 1st-order aldol disconnections highlighted. Lets proceed forward with BH3 Transform: See Lecture No 8 T1B. Carry out the disconnection to Me Me subunits 2K and 2A CrC11 Assemblage a center important Both centers important 1. NaBH(OAc)3 2.(MeO)CMe 2, H For substituted enolate and enolsilane- based processes, there are at least three identifiable stereochemical determinants that influence reaction diastereoselectivity (eq 1). Two of these determinants are associated with the local chirality of the individual reaction partners. For example, enolate(enolsilane)chirality infiuences the (85%)Diastereoselection absolute stereochemistry of the forming methyl-bearing stereocenter, and in a similar H fashion, aldehyde chirality controls the absolute stereochemical outcome of the incipient hydroxyl-bearing stereocenter. The third determinant, the pericyclic OH reactions of metal enolates(M= BR 2, T 3, Li, etc. ) but is absent in the Lewis acid catalyzed( Mukaiyama)enolsilanes aldol variants that proceed via open transition Matched aldol addition Me Sn(otn o al Determinants M= BR2 M= siR3 Et3N Xp 1 enolate facial bias vv aldehyde facial bias Anti-Felkin Adduct Diastereoselection >95: 5 (86%) pericyclic transition state The Sn(oTi)2 aldol reaction of A: seethis lecture+ JACS, 1990, 112, 866M R1 O Me Me R1 O Me Me OH R2 Me H R2 O Me H OMe O Me O Me O HO Me OH Me OH Me O N Me O O Me O Bn OMe Me O Me O HO Me OH Me OH Me O N Me O O Me O Bn a a' a a' 11 11 Me O O XP Me O Me Me Me Me O O XP Me OH Me Me OH Me XP O O Me O O Me Me Me Me HO O O Me OMe Me Me OMe Me OH Me O O O Me Me O O Me OMe Me OMe Me Me OH H H H H O O O Me Me Me Me Me Sn(OTf)2 Sn(OTf)2 Et3N Et3N Me O H A A H R O Me OR Me 2A R R OR O Me Me OR Me Me OH Me OR Me R R OH OH Me Me OR Me Me OH Me OH Me R OR O Me Me OR Me Me 2K T1A T1B R R OH O Me Me OR Me Me OR Me OR Me Synthesis of Polyketide chains D. A. Evans Introduction to Complex Aldol Bond Constructions Chem 206 Given a polyprpionate chain of alternating Me & OH substitutents, select a disconnection point sectioning the fragments into subunits of comparable complexity by adding C=O as illustrated. Focusing on the =O FG, there are 2 1st-order aldol disconnections highlighted. Let's proceed forward with T1B. Carry out the dissconnection to subunits 2K and 2A. a b a' b' aldol a b a' b' a center important b center ignore Both centers important ✔ ✔ ✔ ✘ ✔ ✔ (1) Stereochemical Determinants M = BR2 M = SiR3 enolate facial bias aldehyde facial bias pericyclic transition state For substituted enolate and enolsilane-based processes, there are at least three identifiable stereochemical determinants that influence reaction diastereoselectivity (eq 1). Two of these determinants are associated with the local chirality of the individual reaction partners. For example, enolate (enolsilane) chirality influences the absolute stereochemistry of the forming methyl-bearing stereocenter, and in a similar fashion, aldehyde chirality controls the absolute stereochemical outcome of the incipient hydroxyl-bearing stereocenter. The third determinant, the pericyclic transition state, imposes a relative stereochemical relationship between the developing stereocenters. This important control element is present in the aldol reactions of metal enolates (M = BR 2 , TiX 3 , Li, etc.), but is absent in the Lewis acid catalyzed (Mukaiyama) enolsilanes aldol variants that proceed via open transition states. The Lonomycin Synthesis: An example of polypropionate assembage Evans, Ratz, Huff, Sheppard JACS 1995, 117, 3448 C1–C11 Assemblage 1 3 5 7 9 Swern 86% LiBH4 , EtOH 1. NaBH(OAc)3 2. (MeO)2CMe2 , H+ (85%) Diastereoselection 95 : 5 5 5 9 5 9 5 9 7 7 9 1 3 5 7 9 BH3 Transform: See Lecture No. 8 93% 1 3 1 5 9 Anti-Felkin Adduct Diastereoselection >95 : 5 (86%) The Sn(OTf)2 aldol reaction of A: seethis lecture + JACS, 1990, 112, 866 JACS, 1990, 112, 866 Stereochemically Matched aldol addition