REVIEW 2175 Stereoselective Acetate Aldol Reactions from Metal Enolates StereoselectiveXavier Acetate Aldol Reactions from Metal Enolates Ariza, Jordi Garcia, Pedro Romea,* Fèlix Urpí* Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Catalonia, Spain Fax +34(93)3397878; E-mail: [email protected]; E-mail: [email protected] Received 27 January 2011; revised 24 February 2011 Dedicated to the memory of recently deceased Professor Rafael Suau often contests their capacity to install the required stereo- Abstract: This review deals with stereoselective acetate aldol reac- tions mediated by metal enolates. It summarizes recent advances in centers efficiently. Hence, it has always been seen as aldol additions of unsubstituted metal enolates that either incorpo- highly desirable to achieve parallel transformations from 8 rate chiral auxiliaries, stoichiometric Lewis acids, or catalytic metal enolates. Unfortunately, acetate aldol reactions Lewis acids or bases, or act in substrate-controlled reactions. These mediated by such intermediates can proceed through dif- approaches provide stereocontrolled aldol transformations that al- ferent six-membered cyclic transition states, represented low the efficient synthesis of structurally complex natural products. in Scheme 2, which hampers the proper differentiation of the two faces of the carbon–oxygen double bond by the 1 Introduction 3,9,10 2 Chiral Auxiliaries unsubstituted enolate. Therefore, stereocontrol in 3 Stoichiometric Lewis Acids these reactions relies on the appropriate choice of the met- 4 Catalytic Lewis Acids and Bases al and the chiral elements on the substrate, the aldehyde or 5 Substrate-Controlled Aldol Reactions the ligands (R1, R2, and L, respectively) to provide a single 5.1 a-Methyl Ketones highly organized transition state. 5.2 a-Hydroxy Ketones 5.3 b-Hydroxy Ketones L H 5.4 b-Hydroxy a-Methyl Ketones n M ML m 2 O O O O R 5.5 a,b-Dihydroxy Ketones 2 R CHO 1 1 1 R R 5.6 Remote Stereocontrol R 6 Conclusions metal enolate Key words: stereoselective acetate aldol reactions, metal enolates, M = Li, B, Ti, Sn,... L chiral auxiliaries, Lewis acids, substrate-controlled reactions n O OH M OO 1 2 R R 1 2 R R new carbon–carbon bond 1 Introduction a new stereocenter The development of highly stereoselective aldol method- transition-state geometries 1 R O 2 1 R ologies and their successful application to the synthesis of 2 R R 2 L M O ML n R n ML 2 n R O O structurally complex natural products have placed the al- O O L MO O n 1 R 1 dol reaction among the most important carbon–carbon R boat A boat B twist boat bond-forming processes.1,2 In spite of this, aldol reactions chair from unsubstituted chiral enolates are still a matter of con- Downloaded by: University of Illinois. Copyrighted material. cern.3 Indeed, pioneering studies revealed early on that the Scheme 2 stereochemical control in the acetate aldol reaction (R = H in Scheme 1)4 was much more demanding than for The scope of this overview is limited to the most signifi- its propionate counterpart (R = Me in Scheme 1).5 cant methodologies on stereoselective acetate aldol addi- This challenge is usually countered by the use of tions of chiral metal enolates; that is, it describes the Mukaiyama-like6 and, more recently, organocatalytic ap- reactions in which the chiral elements are located on the proaches.7 Nowadays, there are successful examples of substrate or on the ligands bound to the metal of these in- both methodologies, but the synthesis of natural products termediates. It does not intend to be an exhaustive cover- age of the literature and some other important aspects of O OH O O OH these transformations, such as the influence of aldehyde 3 R3CHO R CHO R2 R1 R3 R1 R1 R3 chirality, are not specifically addressed. R2 = Me R2 = H Me propionate aldol reaction acetate aldol reaction Scheme 1 2 Chiral Auxiliaries SYNTHESIS 2011, No. 14, pp 2175–2191xx.xx.2011 The poor stereocontrol observed in preliminary studies on Advanced online publication: 10.05.2011 aldol reactions from unsubstituted enolates triggered an DOI: 10.1055/s-0030-1260040; Art ID: E15611SS intense search for an efficient, covalently bound chiral © Georg Thieme Verlag Stuttgart · New York 2176 X. Ariza et al. REVIEW 3 1) LDA O OH O Ph auxiliary. Among the large number of reported auxilia- Ph THF, 0 °C OH OH O ries, chiral 1,1,2-triphenylethanediol arising from man- O i-PrCHO 11 2) Ph Ph Ph Ph < –106 °C delic esters, quickly achieved a prominent position. T 1 Indeed, the lithium enolate from acetate 1 (Scheme 3) pro- quant., dr 95:5 vides high yields and diastereoselectivities and has been used successfully in the synthesis of b-hydroxy carbonyl Scheme 3 structures present in natural products.11b,12 cations and the quest for a more general approach However, the extremely low temperatures essential for at- remained active.13,14 Thus, considering that boron eno- taining high diastereoselectivities thwarted further appli- lates from N-acetyl oxazolidinone 2 (Scheme 4) afforded Biographical Sketches Xavier Ariza was born in 1993) and at Stanford promoted to Associate Pro- Barcelona (Spain) in 1966. University (Professor B. M. fessor in 2001. His current He studied chemistry at the Trost, 1996–1997) in the research area is the develop- University of Barcelona, area of asymmetric synthe- ment of stereoselective pro- where he received his PhD sis and organometallic cesses applied to the in 1995 under the supervi- chemistry. In 1998, he synthesis of biologically ac- sion of Professor J. Vilarra- joined the Department of tive compounds, in particu- sa for studies on nucleoside Organic Chemistry of the lar polyols and amino- chemistry. He also worked at University of Barcelona as polyols. ETH (Professor D. Seebach, Assistant Professor and was Jordi Garcia was born in University of Barcelona un- where he is currently Full Barcelona (Spain) in 1956. der the supervision of Professor. His research ac- He obtained a degree in Professor J. Vilarrasa on tivity includes both academ- chemistry in 1979 and an- synthetic organic chemistry. ic and applied projects in the other in pharmacy in 1992 at After postdoctoral studies area of stereoselective the University of Barcelona. with Professor S. Masamune methodology and synthesis After a short stay at the In- at the Massachusetts Insti- of natural products, espe- stitut de Chimie des Sub- tute of Technology (USA) cially those related to boron stances Naturelles (CNRS, working on boron chemis- and palladium chemistry. Gif-sur-Yvette, France) try, he was appointed to the He is also involved in re- working on carbohydrate post of Associate Professor search projects at the inter- chemistry in Professor G. at the Department of Organ- face of biochemistry and Lukacs’ laboratory, he ob- ic Chemistry of the Univer- inorganic chemistry. tained his PhD in 1986 at the sity of Barcelona in 1988, Pedro Romea was born in chemistry. Then, he joined Professor in 1993. His re- Barcelona (Spain) in 1961. the group of Professor Ian search interests have fo- Downloaded by: University of Illinois. Copyrighted material. He studied chemistry at the Paterson at the University of cused on the development of University of Barcelona, Cambridge (UK), where he new synthetic methodolo- where he received his PhD participated in the total syn- gies and their application to in 1991 under the guidance thesis of oleandolide. Back the stereoselective synthesis of Professor J. Vilarrasa for to the University of Barcelo- of biologically active natu- studies on synthetic organic na, he became Associate ral products. Fèlix Urpí was born in Sant worked as a NATO postdoc- 1991. His research interests Sadurní d’Anoia (Spain) in toral research associate in have focused on the devel- 1958. He studied chemistry titanium enolate chemistry opment of new synthetic at the University of Barcelo- with Professor David A. methodologies and their ap- na, where he received his Evans, at Harvard Universi- plication to the stereoselec- PhD in 1988 under the guid- ty (USA). Later, he moved tive synthesis of biologi- ance of Professor J. Vilarrasa back to the University of cally active natural prod- for studies on synthetic or- Barcelona and he became ucts. ganic chemistry. He then Associate Professor in Synthesis 2011, No. 14, 2175–2191 © Thieme Stuttgart · New York REVIEW Stereoselective Acetate Aldol Reactions from Metal Enolates 2177 5a,15,16 S S O OH 1) TiCl , i-Pr NEt O 2 a nearly 1:1 ratio of diastereomers, the unprecedent- 4 Cl , –78 °C CH 2 ed stereocontrol observed by Nagao, Fujita and co-work- 2 O N O N 2) -PrCHO, –78 °C ers in tin(II)-mediated aldol reactions from N-acetyl i oxazolidinethione 317 and thiazolidinethione 418,19 were 86%, dr 94:6 particularly outstanding (Scheme 4). 5 S S O OH 1) TiCl , i-Pr NEt O 4 2 O O O O OH BOTf, i-Pr NEt 1) Bu Cl , –40 °C CH 2 2 2 2 Cl , –78 °C CH 2 2 S N Ph S N 2) PhCH=CHCHO, –78 °C N O N O 2) i-PrCHO, –78 °C 70%, dr 90:10 i-Pr i-Pr 86%, dr 52:48 i-Pr i-Pr 4 2 S S O O OH 1) Sn(OTf) , (C H )NEt 5 10 2 Scheme 6 Cl , –40 °C CH 2 2 N N O O i-PrCHO, –78 °C 2) 25 60%, dr 91:9 pared from natural and unnatural a-amino acids and tita- Et Et 26 3 nium(IV) chloride is a readily available Lewis acid. S S O O OH 1) Sn(OTf) , (C H )NEt 5 10 2 Thus, the stage was set for further developments in this ar- Cl , –40 °C CH 2 2 N N S Ph S ea.