Divergent Synthetic Access toE- andZ-Stereodefined All-Carbon-Substituted Olefin Scaffolds: Application to Parallel Synthesis of (E)- and (Z)-Tamoxifens

Abstract

A highly substrate‐general synthesis of all‐carbon‐substituted E‐ and Z‐stereodefined olefins is performed. The method comprises two sets of parallel and stereocomplementary preparations of (E)‐ and (Z)‐α,β‐unsaturated esters involving two robust and distinctive reactions: 1) stereocomplementary enol tosylations using readily available TsCl/diamine/(LiCl) base reagents, and 2) stereoretentive Negishi cross‐coupling using the catalysts [Pd(dppe)Cl2] (for E) and [Pd(dppb)Cl2] (for Z). The present parallel approach is categorized as both type I (convergent approach: 16 examples, 56–87 % yield) and type II (divergent approach: 18 examples, 70–95 % yield). The obtained (E)‐ and (Z)‐α,β‐unsaturated ester scaffolds are successfully transformed into various E‐ and Z‐stereodefined known and novel olefins (8×2 derivatization arrays). As a demonstration, application to the parallel synthesis of both (E)‐ and (Z)‐tamoxifens, a representative motif of all‐carbon‐substituted olefins, is accomplished in a total of eight steps with an overall yield of 58 % (average 93 %) and 57 % (average 93 %), respectively.

Regio- and stereoselective synthesis of tetra- and triarylethenes by N-methylimidodiacetyl boron-directed palladium-catalysed three-component coupling

“…Platform synthesis is a powerful strategy to realize the synthesis of complex molecules in a programable and diversity-oriented format. In this regard, the advances of metal catalysis have inspired tremendous efforts towards modular tetraarylethene construction starting from alkenes [11][12][13][14][15][16][17] or alkynes [18][19][20][21][22][23][24][25][26] . Nevertheless, lengthy synthetic operations, the poor functional group tolerance arising from the participation of organolithium or Grignard reagents, and the often-encountered poor regioselectivity strongly limits their practical application.…”

(E)‐,(Z)‐Stereodefined α‐Chloro‐β‐tosyloxy‐α,β‐unsaturated Esters: Sequential Cross‐Couplings for (E)‐,(Z)‐Stereo Complementary Synthesis of Fully‐Substituted α,β‐Unsaturated Esters

“…Following the procedure for the preparation of (E)-3 a, the reaction of enol tosylate (E)-1 b (3.67 g, 10.0 mmol) using (p-Me)C 6 H 4 B(OH) 2 (1.63 g, 12.0 mmol), Pd(OAc) 2 (112 mg, 0.500 mmol), PPh 3 (262 mg, 1.00 mmol), and K 2 CO 3 (1.66 g, 12. 1,138.6,139.2,147.9,165.7;IR (neat): 3059,2953,1722,1597,1379,1298,1177,1045,804,733 [8,11] Following the procedure for the preparation of (Z)-4 c, the reaction of enol tosylate (E)-3 a (105 mg, 0.50 mmol) using PhB(OH) 2 (73 mg, 0.60 mmol), Pd(OAc) 2 (1.1 mg, 0.005 mmol), SPhos (2.0 mg, 0.005 mmol), and K 2 CO 3 (83 mg, 0.60 mmol) gave the desired product [(Z)-4 a, 112 mg, 89%, E/Z = 2 : > 98]. pale yellow oil; 1 H NMR (300 MHz, CDCl 3 ): δ = 2.05 (s, 3H), 3.43 (s, 3H), 7.29-7.44 (m, 10H); 13 C NMR (75 MHz, CDCl 3 ): δ = 22.2, 51.…”

“…5, 126.8, 127.5, 128.1, 128.3, 129.1, 132.5, 137.1, 142.8, 143.9, 169.6. [8,11] Following the procedure for the preparation of (Z)-4 c, the reaction of enol tosylate (Z)-3 a (105 mg, 0.50 mmol) using PhB(OH) 2 (73 mg, 0.60 mmol), Pd(OAc) 2 (1.1 mg, 0.005 mmol), SPhos (2.0 mg, 0.005 mmol), and K 2 CO 3 (83 mg, 0.60 mmol) gave the desired product [(E)-4 a, 113 mg, 90%, E/Z = > 98 : 2]. pale yellow oil; 1 H NMR (300 MHz, CDCl 3 ): δ = 2.36 (s, 3H), 3.76 (s, 3H), 6.95-7.18 (m, 10H); 13 C NMR (75 MHz, CDCl 3 ): δ = 23.2, 51.…”

“…The obtained ( E )‐ and ( Z )‐enols function as reliable ( E )‐ and ( Z )‐stereoretentive cross‐coupling partners as described in two subjects in Organic Syntheses . In particular, the method utilizing enol ( E )‐ and ( Z )‐tosylates was successfully applied to concise ( E )‐ and ( Z )‐parallel syntheses of zimelidines and tamoxifens, which are representative probes for the multi‐substituted olefin product. In addition, we performed ( E )‐ and ( Z )‐stereocomplementary synthesis of a key pharmacophore, recently developed by Merck's group .…”

Straightforward Synthesis of N-Methyl-4-(pin)B-2(3H)-benzothiazol-2-one: A Promising Cross-Coupling Reagent

“…Our recent interest in cross-coupling reactions, directed towards medicinal and process chemistry, [18][19][20][21][22], led us to investigate a concise synthesis of novel 4-(pinacolato)borane (pin)B derivative 3 derived from N-methyl-4-bromo-2(3H)-benzothiazol-2-one (5), which could serve as a convenient substrate for Suzuki-Miyaura cross-coupling reactions ( Figure 2). A literature survey using SciFinder ® revealed that a 6-(pin)B analogue was reported as the synthetic intermediate for: (1) inhibitors of matrix metalloproteinases (MMPs) and the production of tumor necrosis factor α (TNF α) [23]; (2) treatment of inflammatory respiratory diseases [24]; (3) modulators of aldosterone synthase and/or 11-β hydroxylase [25]; and (4) inhibitors of IKKβ (IκB Kinase-β) kinase [26].…”