DOI: 10.1002/anie.200((will be filled in by the editorial staff)) Multifunctional C3-Homologation Acetylide salts of alkyl propiolates: privileged three-carbon homologating building blocks** David Tejedor,* Sara López-Tosco, Fabio Cruz-Acosta, Gabriela Méndez-Abt and Fernando García-Tellado* Dedicated to Professor George W. Kabalka on the occasion of his 65th birthday Alkyl propiolates constitute a privileged group of C3-homologating agents with a rich and plural reactivity profile that entirely remains in the homologated product for further elaboration. To be effective, this C3-homologation requires a suitable methodology for the generation of the acetylide anion of the alkyl propiolate compatible with both the conjugated ester and the electrophilic partner. Recent advances in this direction include metal and metal-free catalytic protocols for the in situ generation of these acetylides in the presence of suitable electrophiles. Whereas the organometallic protocols have brought stereoselectivity to these reactions, the organocatalytic methods have settled the bases for new efficient and complexity generating domino processes. 1. Introduction [1] Among the large list of available C3-homologation agents, alkyl a) Polyvalent reactivity profile [2] propiolates (HCC-CO2R) maintain a privileged place in the light 1 [3] Labile d0 a [1,2-addition] of the latest tendencies in drug discovery research. This C3-unit 2 3 2 a [α-addition] 0 1 2 [4] 3 a a a1 O exhibits a rich and polyvalent reactivity profile (i.e., d , a , a , a , H a3 [1,4-addition] 3 3 2 [5] d3 d2 3 d and [a +d ]; Figure 1a) which entirely remains in the OR d [ C3-Homologation] homologation product (with the obvious exception of d3). Among [a3+d2] [Cycloaddition] [Baylis-Hillman] other applications, this chemically rich C3-functionality can be used [β-Oniovinylation] as handle for the generation of structural complexity and diversity in 3 the homologated molecule (Figure 1b). Central to this issue is the b) Reactivity: d Action: C3-Homologation Attachment group O OR O OR X Activator Chemical [∗] Tenured Scientist David Tejedor, Sara López-Tosco, Fabio Y and/or handle Cruz-Acosta, Gabriela Méndez-Abt and Research catalyst HX Y H Scientist Fernando García-Tellado C3HU Instituto de Productos Naturales y Agrobiología-CSIC Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, Canary Islands, Spain Fax: (+)34922-260135 Figure 1. C3-Homologation reaction with alkyl propiolates (C3HU = C3- E-mail: [email protected]; [email protected] Homologating Unit). Homepage: http://www.ipna.csic.es/departamentos/qbb/qb/ Dr. David Tejedor and Dr. Fernando García-Tellado are development of a suitable methodology for a selective d3-reactivity associate researchers at the Instituto Canario de performance, which basically demands the generation of an Investigación del Cáncer (www.icic.es). acetylide anion and its nucleophilic addition into the appropriate [∗∗] This research was supported by the Spanish Ministerio de electrophile. Ideally, these acetylides would be generated in situ, in Educación y Ciencia and the European Regional a catalytic manner and in such a way that the nucleophilic addition Development Fund (CTQ2005-09074-C02-02). F.G.-T. thanks Fundación Instituto Canario de Investigación del Cáncer for financial support (FICI-G.I.Nº08/2007). S.L.-T. thanks Spanish MEC for a FPU grant. Authors thank Dr. 1 Tomás Martín and Dr. Pedro de Armas for helpful discussions and critical reading of this manuscript. is compatible with both the conjugated ester functionality and the O R1 RO2C electrophile. Under these conditions, the incorporated C3-unit could 1 RO C 3 R 2 be directly submitted to new homologating or complexity generating R N OH 1 2 C 2 R reactions without needing functionality reconstitution. Classical O O N 2 ( R methodologies have exploited the high acidity of the terminal M N e 1 acetylenic C-H bond (pKa ≤ 18.8) to form the metal conjugated )O R [6] M CO R alkynylide by treatment with strong bases such as n-butyllithium e 2 or lithium diisopropylamide (LDA).[7] Although these protocols are CO2R CO2R 2 CO compatible with the alkyl propiolate, they cannot be performed in 1 R 2 A or B R HO R the presence of base-sensitive substrates such as aldehydes or R1 ketones. This chemical incompatibility obliges to perform the M R2 1 alkynoate deprotonation in a separate and previous step to the C-C l N bond forming reaction. Thus, other protocols more according with C COMe O [8] C the latest tendencies in organic synthesis would be desirable to h 2 P R fully exploit the chemical advantages associated with these Ph OH N homologating building blocks. Additionally, and not less important, COMe the design of new methodologies requires overcoming two chemical 5 RO2C 4 CO2R difficulties associated with the electronic nature of these C3-units: the low nucleophilicity of these carbanions and the marked CO2R electrophilicity of the conjugated triple bond (a3-reactivity). The A: BuLi or LDA, THF, -78ºC (R = Et) or -100ºC (R = Me) first limits both the scope of the electrophilic partner and the type of B: two steps: 1) A; 2) Transmetallation with MXn C-C bond forming process in which they can participate, whereas the second restricts the nature of the metal and/or the base required Scheme 1. Generation and addition of metallic acetylides to electrophiles. to form the ylide. Recent advances in this field include both metal and metal-free catalytic protocols for the in situ generation of the acetylide anions. W hile the organometallic protocols have achieved 2.2. Silver acetylides. Bench stable acetylide anions of alkyl stereoselectivity, metal-free methodologies have settled the bases for propiolates. new efficient and complexity generating domino processes. Koide and col. have reported the use of the bench-stable silver acetylide 6 as a synthetic alternative to the lithium salt of methyl 2. Metallated acetylide salts of alkyl propiolates. A propiolate. The acetylide is readily prepared from methyl propiolate successful journey to asymmetric catalysis. in multigram scale (≈8g) (Scheme 2)[26] and it can be stored in a vial for months without special precautions.[27] 2.1. Lithium acetylides: the classical homologating agent. CO2Me Substrate- controlled diastereoselective C -homologation. CO2Me 3 AgNO3 (2.1 equiv) NH4OH, H2O/MeOH 7ithium acetylide salts of methyl or ethyl propiolates constitute the 23ºC, 20 min, 98% Ag standard source of metallated acetylides (d3-reactivity). They are 6 prepared by Midland‘s method6 and they are relatively stable when [9] kept at low temperature (Scheme 1). In spite of their weak Scheme 2. Preparation of the bench-stable silver acetylide 6. nucleophilicity and the low temperatures required to obtain them, these acetylides add to aldehydes and ketones to give the propargylic alcohols 1 in good yields.[10] Other electrophiles such as As expected for alkynyl silvers,[28] these acetylides exhibit low nitrones,[11-13] acid chlorides,[14] W einreb amides,[15],[16] and basicity and extreme mildness, requiring a stoichiometric amount of [17] acylpyridium ions have also proved accessible to these anions Cp2ZrCl2 and a catalytic amount of AgOTf to react with aldehydes (Scheme 1). Less active electrophiles require the use of co- (Scheme 3).[29],[30] The benefits of this protocol have been activators or the replacement of lithium for other more effective demonstrated by Koide‘s group in the synthesis of the antitumor metals (transmetallation) (magnesium,[18] zinc,[19-22] cerium[23] or agent FR901464.[31] A very recent report from this group has also [24] boron ). W ith regard to stereoselectivity, these C3-homologations extended this protocol to the synthesis of propargylic alcohols by a are substrate-controlled and good diastereoselectivity levels can be zirconium-promoted tandem epoxide rearrangement-alkynylation [27] achieved by convenient combinations of chiral auxiliary and reaction. [25] metal. 6 (1.6 equiv) [Cp2ZrCl2] (1.2 equiv) R1CHO 1 [R2 = H] AgOTf (0.2 equiv) 60-93% 23ºC, CH2Cl2 R = Alk, Ar Scheme 3. (Cp2ZrCl2)-AgOTf promoted addition of silver acetylides to aldehydes . 2 2.3. Zn and copper acetylide salts of alkyl propiolates. Catalytic formation, is considerably faster (times reduced from 16 h to 7 h). enantioselective C3-homologations. Scheme 7 outlines the mechanistic proposal for this catalytic system. The catalytic generation of metal acetylides under conditions compatible with electrophilic reaction partners had been a long term unresolved synthetic challenge.[32] A main breakthrough came from 1) (S)-9 (30 mol%), CO2Me Et2Zn (3 equiv)DME (1 equiv), Carreira‘s group with the first asymmetric addition of zinc 1 [R2 = H] [33] acetylides to aldehydes (Scheme 4). Although the system works Toluene, RT, 7h 64-80% 2) Ti(OiPr)4 (30 mol%), 0.5h 79-94% ee 3) RCHO (1equiv), 9-15h OH Zn(OTf) Et N RCHO 2, 3 R Bn Et 23ºC, toluene MeO Et 1 R Ph Me TolSO2HN OH 7 R1 OMe (S)-9 DME HO NMe2 35-99% 30-99% ee 1 R = Alk; R =Alk, Ar Scheme 6. Enantioselective addition of methyl propiolate to aldehydes catalyzed by β−sulfonamide alcohol (S)-9. Scheme 4. Enantioselective addition of in situ generated zinc alkynylides to aliphatic aldehydes. Step 1: zinc alkynylide formation Ethane Bn efficiently with a wide number of terminal alkynes, alkyl propiolates Et Bn Et Et Et lead to decomposition when they are exposed to these reaction O Zn Et O Zn Et O conditions. This drawback has been elegantly overcome by Pu and Tol S N O Tol S N O Zn O Zn col. with the development of their binol-titanium-based catalytic Et Et Et Et Zn system.[34] The reaction utilizes (1)-1,1‘-bi-2-naphtol ((1)-7) as the Zn H Z Et A Z chiral ligand, titanium tetraisopropoxide (Ti(OiPr)4) as a Lewis acid B activator and hexamethylphosporamide (HMPA) as a Lewis base additive.[35] The catalytic system is performed in a one pot manner iPrO Zn Et Ti(OiPr)4 and it comprises two synthetically differentiated steps: 1) the Step 2: alkynylide additon alkynylzinc formation and 2) the alkynylide transfer to furnish the RCHO Bn corresponding 4-hydroxy-J,K-acetylenic product 1 in good yields D Et Bn Et Et Et (55-96%) and high enantioselectivity (87-95% ee) (Scheme 5).