Stereocomplementary and Parallel Syntheses of Multi‐Substituted (E)‐, (Z)‐Stereodefined α,β‐Unsaturated Esters: Application to Drug Syntheses

Ubiquitous α,β‐unsaturated esters are well recognized as key structural olefin scaffolds in organic chemistry. (E)‐ and (Z)‐steroselectivity is the most critical issue in their synthesis, however, (E)‐ and (Z)‐ stereocomplementary synthetic methods remain quite limited. The present account discloses general (E)‐, (Z)‐stereocomplementary syntheses of a variety of α,β‐unsaturated esters from highly accessible (E)‐, (Z)‐stereodefined enol tosylates derived from β‐ketoesters and α‐formyl esters. Step 1 toward the stereocomplementary preparation of (E)‐, (Z)‐stereodefined enol tosylates is implemented by using inexpensive reagents under mild reaction conditions. Step 2 toward the highly stereoretentive synthesis of (E)‐ and (Z)‐stereodefined α,β‐unsaturated esters involves Suzuki‐Miyaura, Negishi, Sonogashira, Iron‐catalyzed, Mizoroki‐Heck, and Buchwald‐Hartwig cross‐coupling reactions. Notably, this strategy was successfully applied for parallel drug syntheses of (E)‐ and (Z)‐zimelidine, (E)‐ and (Z)‐tamoxifen, and Merck's cyclopropane pharmacophore. Representative successful utilizations by other groups are also introduced.


Introduction
Regio-and stereo-controlled syntheses of ubiquitous (E)-and (Z)-stereodefined olefins are of particular importance in organic chemistry due to the wide distribution of these key structural components in natural products, pharmaceuticals, and functionalized molecules. Despite numerous available methods for synthesizing these olefins, the development of stereoselective syntheses of multi-carbon-substituted olefins has become a pivotal goal aimed at enhancing both (E)-and (Z)stereoselectivity and facilitating separation of the stereoisomers. [1,2] (E)-and (Z)-α,β-Unsaturated esters serves as a well-recognized, useful, and accessible structural scaffolds for various (E)-and (Z)-stereodefined olefins. These esters contribute asymmetric hydrogenation precursors and conjugate (Michael) addition acceptors, etc.
Despite the high demand, however, "(E)-and (Z)-stereocomplementary" synthetic methods for multi-substituted (E)and (Z)-α,β-unsaturated esters are not yet established primarily due to the inherent high complexity in differentiating the substituents. Cross-coupling reactions with (E)-and (Z)stereodefined enol sulfonate and phosphonate [10] partners derived from β-ketoesters, which emerged in the last few decades, are considered a promising, accessible, and reliable approach compared with the above-mentioned methods and have the following advantages. (i) Various starting β-ketoester substrates are readily available, (ii) (E)-and (Z)-stereocomplementary enol tosylation step is robust and costeffective, [11,12] and (iii) (E)-and (Z)-stereoretentivity during the cross-coupling step is guaranteed owing to recent developments in cross-coupling reactions.
This account describes our recent investigations on stereocomplementary and parallel syntheses of (E)-and (Z)-α,βunsaturated esters derived from β-ketoester and α-formylester substrates (Scheme 2), in which the strategy is categorized into convergent-oriented type-1 and divergent-oriented type-2 approaches. Distinctive application to parallel syntheses of two sets (all four) of pharmaceuticals, (E)-and (Z)-zimeridine and (E)-and (Z)-tamoxifen, are also demonstrated.

Origin and Motif
The p-toluenesulfonyl (Ts-) group is a well-established leaving group against various nucleophiles, and the reaction is recognized as textbook chemistry. Tosylation (p-toluenesulfonylation) of alcohols using TsCl in pyridine solvent is the most traditional method [See Supporting Inforormation (SI)].
Our 5 alternative methods for mild but powerful, costeffective tosylation and the relevant mesylation (Ms-) (Methods A-E) [13] are depicted in Scheme 3. These methods are utilized for natural product and functionalized material syntheses such as (+)-vinblastine from Fukuyama and Tokuyama's group, [14] flourlescent amino acid precursor from Nau's group, [15] and industrial production of a brockbuster herbicide, flumioxadine, by the Sumitomo Chemical group. [16] To date, there are over 100 exemplary applications indexed in the Web of Science®.
Our group has been engaged in the research and development of self, crossed, and asymmetric Ti-Claisen condensations for the preparation of a wide variety of β-ketoesters and α-formyl esters (Selected Abstract: Scheme 4). [17] The syner-gistic background of these longstanding interests of ours prompted us to envisage the present project.

"α-Nonsubstituted" β-Ketoesters and α-Formyl Esters
In 2005, the Merck process group disclosed (E)-and (Z)stereocomplementary enol tosylations of specific γ-amino-βketobutylates (GABA analogues) using a Ts 2 OÀ Et 3 N reagent for the E geometry and an expensive Ts 2 OÀ LDA reagent for the Z-geometry. [11] TsCl is ca.1/10 less expensive than Ts 2 O, but use of the TsClÀ LDA reagent causes α-chlorination at the methylene position as a critical side reaction. [11b] Instead of using expensive reagents (Ts 2 O and LDA) and a low temperature (À 50°C), our methods employ a much more accessible and robust procedure (reagent stability and benchtop handling) using a TsCl-N-methylimidazole (NMI)À Et 3 [12] (Table 1; Selected and other examples). The method covers various α-nonsubstituted β-ketoesters and α-formyl esters. A relevant (E)-and (Z)-stereocomplementary enol triflation was presented by Frantz's group in the same year. [18] Notably, NMI activator also functions well as an efficient activator for various condensation reactions, O-, N-, and Sacylations (esterification, amide formation, thioesterification) (Scheme 5), [19] and distinctive C-acylation (crossed Ti-Claisen condensation). [17e,h] The method in Scheme 5 has been utilized for ester and His research focuses on the exploitation of useful synthetic reactions directed for process chemistry: concise synthesis of useful fine chemicals and of total synthesis of biologically active natural products.
amide forming reactions in recent drug syntheses and functional molecule.

Mechanistic Explanation for the E-and Z-Selectivity Emergence
TsCl coupled with NMI and TMEDA are speculated to form key highly reactive sulfonylammonium salts I and IIA, respectively, which was supported by findings from a careful 1 H-NMR monitoring experiment (À 40°C in CD 3 CN) [20] (Scheme 6, 1 H-NMR charts are shown in the SI). A plausible mechanism for the successful emergence of (E)-and (Z)stereoselectivity is as follows. The (E)-reaction proceeds via a non-chelation pathway, whereas the (Z)-reaction proceeds via a Li-chelation mechanism. [22]

Stereoretentive Cross-Coupling Reactions of (E)and (Z)-Stereodefined Enol Tosylates
These (E)-and (Z)-stereodefined enol tosylates function as various efficient stereoretentive cross-coupling partners. Despite the considerable demand for multi-substituted α,β-unsaturated (E)and (Z)-stereodefined esters on the synthesis of natural products, pharmaceuticals, and supramolecular assemblies, there are no fully established stereocontrolled and substrate-general preparative methods due to the fundamental difficulties in differentiating between structurally similar substituents. The following methods provide reasonable solutions to this crucial demand.

(E)-and (Z)-Sterecomplementary Negishi Cross-Coupling Reactions
In  (Table 5; Selected and other examples). The Pd(dppe)Cl 2 catalyst was employed for an Estereoretentive reaction and, whereas the Pd(dppb)Cl 2 catalyst was employed for and Z-stereoretentive reaction. Various aromatic substituents (Ar) were incorporated and some functional groups were tolerated. Throughout this project, we observed that Negishi cross-couplings tends to exhibit somewhat higher reactivity with lower catalyst loading than SM cross-couplings.  (Table 6). The present method provides a practical synthesis of less accessible (Z)-α,β-unsaturated esters, as exemplified in Organic Syntheses procedure (Scheme 8). [26] Extensions of Suzuki-Miyaura and Negishi couplings to aliphatic nucleophiles were not examined, but to overcome the limitation a Fe-catalyzed reaction method was addressing this problem.

Parallel and Stereocomplementary Synthesis: Application to (E)-and (Z)-Zimelidine
A highlighted feature of the present project is the use of "parallel and stereocomplementary approaches" to furnish highly (E)-and (Z)-pure olefinic products utilizing sequential enol tosylations and cross-coupling reactions. An expeditious and parallel synthesis of (E)-and (Z)-zimelidines, a highly representative selective serotonin reuptake inhibitor (SSRI), was performed (Scheme 10, Table 4). [22] The salient features are as follows:  I and II). Compared with the reported synthesis of (E)-and (Z)-zimelidines, [28] the present method is of highly concise and orthogonal, and eliminates tedious pH-dependent separation. Table 3. (E)-and (Z)-stereocomplementary enol tosylations of αchlorinated" β-ketoesters.
A plausible mechanism for the stereo-switch reaction pathways is proposed (Scheme 14). ArPdLnR (Ln = XPhos or SPhos) intermediate III derived from (E)-I is initially formed the single-bond rotation by equilibrium, the stereoinversion product (Z)-II is produced through ArPdLnR intermediate VI.
Although the concrete reason for the ligand effect is currently unclear, our method B using SPhos catalysis sufficiently retarded the (E) to (Z) stereoinversion. [30,31]
As a successful application, a 3-step straightforward synthesis of strobilurin A was performed utilizing the present reaction sequence (dehydration type Ti-Claisen condensation and Suzuki-Miyaura cross-coupling), wherein the geometry of the three consecutive olefins (2E,3Z,5E) was completely maintained.
We believe that the present methodology opens a distinct avenue for the syntheses of multi-substituted (E)-, (Z)-stereodefined α,β-unsaturated esters in the fields of natural product synthesis, pharmaceutical screening, functionalized molecule synthesis, and process chemistry.
Although enol tosylates has strong advantages (reasonable reactivity, economy, stablity, accessiblity), as a future perspective the use of more atom-economic substrates such as enol acetates (-OAc), methoxy acetates (-OMe), and ideally intact much available β-ketoesters are challenging projects.