α-Ketophosphonates as Ester Surrogates: Isothiourea-Catalyzed Asymmetric Diester and Lactone Synthesis

Abstract

Isothiourea HBTM-2.1 catalyzes the asymmetric Michael addition/lactonization of aryl-and alkenylacetic acids using -keto-,-unsaturated-phosphonates as ,-unsaturated ester surrogates, giving access to a diverse range of stereodefined lactones or enantioenriched functionalized diesters upon ring-opening.Lewis base organocatalysis has developed as a powerful tool for the enantioselective construction of carbon-carbon bonds. 1 Within this area, the asymmetric addition of enolates and their derivatives via the use of cinchona alkaloids, 2 enamines 3 and azolium enolates 4 generated with Nheterocyclic carbenes (NHCs), 5 to electron-deficient alkenes has received wide-spread attention in recent years. Catalytic asymmetric conjugate additions employing enones and enals is well established, 6 although the use of ,-unsaturated esters and amides remains challenging due to the intrinsic decreased reactivity of these motifs. Efforts to circumvent this issue have used N-acylpyrroles, 7 2-acyl imidazoles 8 and activated imides 9 as ester surrogates, while Evans 10 and Jørgensen 11 have pioneered the use of -keto--unsaturated phosphonates as ester equivalents. Using transition metal and organocatalysts respectively, these methods activate the -ketophosphonate for nucleophilic attack via bidentate coordination of a Lewis acid or hydrogen-bonding to a thiourea catalyst architecture (Scheme 1).Building on Romo's pioneering nucleophilecatalyzed aldol lactonization (NCAL) strategy, 12 we have previously studied the isothiourea 13 catalyzed asymmetric functionalization of carboxylic acids 14 via ammonium enolates. 15 This process requires highly electron deficient alkene components in Michael-lactonisation reactions, with ,-unsaturated esters inert to typical reaction conditions. This manuscript explores -ketophosphonates as ,-unsaturated ester equivalents, 16 affording stereodefined diesters upon ring-opening that are suitable for further synthetic manipulations. Scheme 1. Initial conceptInitial investigations employed phenylacetic acid 1 and -ketophosphonate 2 in a model system and assessed a range of isothiourea Lewis base catalysts (5-7, Table 1). In situ formation of the mixed anhydride with pivaloyl chloride and i-Pr 2 NEt, followed by treatment with isothiourea 5 gave anti-lactone 3 in 66% isolated yield with modest ee (entry 1). A screen of isothioureas revealed HBTM-2.1 7 as the optimum catalyst, providing lactone 3 in 86% ee (entry 3). This catalyst was then examined using toluene and THF as the solvent, affording decreased isolated yields but with high diastereocontrol (entries 4-5). Lowering the temperature to 78 °C (entry 6) led to improved isolated yield, dr and ee. Gratifyingly, a catalyst loading of only 1 mol % at 78 °C gave the product in good yield with excellent stere-

Synthesis and biological evaluation of phloroglucinol derivatives possessing α‐glycosidase, acetylcholinesterase, butyrylcholinesterase, carbonic anhydrase inhibitory activity

“…Yield: 80%; 1 H NMR (400 MHz, CDCl 3 ) δ 7.43–7.31 (m, 2H), 7.01 (t, 2H, J = 8.7 Hz), 6.59 (d, 1H, J = 15.9 Hz), 6.29 (dt, 1H, J = 15.9, 5.7 Hz), 4.32 (d, 2H, J = 5.7 Hz). The 1 H NMR spectrum is in agreement with reported data …”

Masked Unsaturated Esters/Amides in Asymmetric Organocatalysis

“…Another interesting example involves the covalent activation of α‐enolizable carboxylic acids 40 employing catalyst XIII 20. This activation strategy renders a catalyst‐bound reactive enolate species, which readily reacts with 4 to form an intermediary lactone.…”

Organocatalytic Michael addition–lactonisation of carboxylic acids using α,β-unsaturated trichloromethyl ketones as α,β-unsaturated ester equivalents

“…The absolute and relative stereochemistry of diester 10 was confirmed by comparison of data with that previously reported, with all subsequent compounds assigned by analogy. 13 Ph Next, a one-pot Michael addition-lactonisation followed by in-situ ring-opening with methanol was trialled (Scheme 2i). In this case major anti-diester 10 was obtained in 78% yield in >99% ee.…”

“…[9][10][11][12] Of particular relevance is our recent report on the use of keto-β,γ-unsaturated phosphonates as ester equivalents in an intermolecular Michael addition-lactonisation reaction, giving access to a range of diester products with high levels of stereoselectivity after ring-opening and alcoholysis. 13 However, many -keto-β,γ-unsaturated phosphonates are not bench-stable and cannot be stored for long periods of time. To alleviate this problem the use of α,β-unsaturated trichloromethyl ketones as alternative, bench-stable α,β-unsaturated ester equivalents seemed an attractive possibility.…”

“…This is in contrast to the use of -keto-β,γunsaturated phosphonates where both ring-opening and either alcoholysis or aminolysis of the phosphate group proceeds rapidly and differential functionalisation is not possible. 13…”