Michael lactonization

Scheme 7.80 Asymmetric synthesis of 3,4-dihydropyran-2-ones by cascade Mukaiyama Michael/lactonization.

In 2013, the Hui group developed an efficient NHC-catalyzed stereoselective aza-Michael-Michael-lactonization cascade reaction of 2-amino phenyl-enones and 2-bromoenals. Functionalized tetrahydroquinolines with three consecutive stereogenic centers were obtained in high yields with excellent diastereo- and enantioselectivity. This approach is attractive due to the mild reaction conditions and the potential application of the products in medicinal chemistry. In addition, this strategy extends the scope of NHC catalysis and provides a simple protocol for the NHC-catalyzed cascade reaction (Scheme 7.100). 

Scheme 7.100 NHC-catalyzed asymmetric aza-Michael-Michael-lactonization cascade reaction of 2-bromoenals with 2-amino phenylenones reported by Hui.

SCHEME 16.21. Enantioselective Michael/lactonization domino reaction. 

Optically active dihydropyranones were synthesized by Smith and co-workers [43] by a highly stereoselective chiral isothiourea-catalyzed intermolecular Michael/lactonization cascade from arylacetic acids and p,7-unsaturated a-ketoesters (Scheme 16.21). This strategy is based on the generation of chiral enolate directly from carboxylic acid activated by the in situ formation of a mixed anhydride and the organocatalyst. 

Aza-Michael-Michael-lactonization domino reaction of 2-bromoenals (308) with 2 -aminophenylenones (309), catalysed by the NHC (306), has been reported to produce tetrahydroquinolines (310) with <99% ee and >25 1 drP ... 

Scheme 7.54 Domino Michael-lactone-opening-aldol-dehydration reaction catalysed by chiral amine catalysis and platinum catalysis followed by esterification.

Ramachary, D. B., Madhavachary, R., Prasad, M. S. (2012). Observation of neighboring ortho-hydroxyl group participation in organocatalytic asymmetric sequential Michael-lactonization reactions synthesis of highly substituted chiral spirodihydro-coumarins. Organic Biomolecular Chemistry, 10, 5825-5829. 

Each of these approaches may be the best for any given lactone the one in the last frame for example would allow you to use any Michael acceptor and any aldehyde. 

A variety of Michael donors such as ketones, esters, thioesters, amides, lactones and lactams may be used and in all of these cases the problems of stereoselectivity apply. 

Lactones have been ultilized as donors, as well as acceptors, in Michael additions giving products with excellent diastereoselectivity. Once the 7>faces of the enolate or the oi,/ -unsatu-rated lactone are effectively shielded by an appropriate substituent at a stereogenic center a to the olefin moiety, this results in the exclusive formation of the Irons-adduct. 

Efficient methods for the production of tetrahydro-5-oxo-3-furanalkanoates use chiral lactones based on 2(5//)-furanones as Michael acceptors110-114 (see Section 1.5.2.4.1.2.5.). For... 

A proline derived chiral nickel complex 1 may be used instead of oe,/J-unsaturated esters of lactones modified with a chiral alcohol as the Michael acceptor. The a,(9-unsaturated acid moiety in 1 reacts with various enolates to afford complexes 2 with diastereomcric ratios of 85 15 to 95 5. Hydrolysis of the imine moiety yields the optically active /(-substituted r-alanines. A typical example is shown296. 

Highly diastereoface selective Michael additions to chiral cycloalkenones and lactones have been developed264. The selectivity is, in general, due to the shielding of one of the diastereotopic faces by a substituent R at the stereogenic center in the y- or -position (steric effect). 

The use of enantiomerically pure (R)-5-menthyloxy-2(5.//)-furanone results in lactone enolates, after the initial Michael addition, which can be quenched diastereoselectively trans with respect to the /J-substituent. With aldehydes as electrophiles adducts with four new stereogenic centers arc formed with full stereocontrol and the products are enantiomerically pure. Various optically active lactones, and after hydrolysis, amino acids and hydroxy acids can be synthesized in this way317. 

An intramolecular version of enolate Michael addition to enantiomerically pure vinylic sulfoxides is represented by reaction of a cyclopentenone sulfoxide with dichloroketene (Scheme 5)90 this type of additive Pummerer rearrangement has been developed by Marino and coworkers91 into a highly effective way of constructing variously substituted lactones in very high enantiomeric purity (equation 43). 

Example The lactone (8>, needed for a natural product synthesis, might be made from (6) via epoxide (7) and so a synthesis for (6) was required. Wittlg disconnection reveals a 1,5-dicarbonyl compound (9), best made by Michael addition of a substituted malonate (11) to enone (10). The enone was made by the simple but reliable Grignard route rather than risking a Mannich reaction of unknown regloselectivity. 

The synthesis of a local anaesthetic required amino lactone (56) as intermediate. The amino groups could be made from a ketone, but if we use a nitro group instead (57) a reverse Michael disconnection gives a simple condensation product (58). 

The combination of CsF with Si(OMe)4 58 is an efficient catalyst for Michael additions, e.g. of tetralone 130 to methacrylamide, followed hy cyclization of the addition product to the cyclic enamide 131 in 94% yield [67]. Likewise, addition of the lactone 132 to methyl cinnamate affords, after subsequent cyclization with tri-fluoroacetic acid, the lactam 133 in 58% yield [68] whereas < -valerolactam 134, with ethyl acrylate in the presence of Si(OEt)4 59/CsF, gives 135 in 98% yield [69]. Whereas 10mol% of CsF are often sufficient, equivalent amounts of Si(OEt)4 59 seem to be necessary for preparation of 135 [69] (Scheme 3.11). 

Scheldt and co-workers have also accessed enolate equivalents from enals to furnish cyclopentanes 236 asymmetrically. Formation of the enolate equivalent from enals 235 with the NHC, followed by an intramolecular Michael reaction and 0-acylation, gives the lactone products 236, which are readily opened by either alcohols or amines to generate functionalised cyclopentane derivatives 237 in excellent ee. 

Mechanistically, a-methylenecyclopentenone (2-391) reacts with ester enolate 2-392 in a Michael addition to give the enolate 2-393, which is then trapped with an aldehyde 2-394 generating the alcoholate 2-396. This eventually cyclizes through lactonization to afford 2-397 in good yield. The products 2-397 are obtained as single diastereomer thus, it can be assumed that the aldol reaction proceeds via the six-membered chair-like transition state 2-395. 

Scheme 2.94. Stereoselective domino Michael/aldol/lactonization process.

One of the best methods to synthesize cyclopentenone derivatives is the Pauson-Khand procedure. However, Shindo s group have recently developed a domino process consisting of a [2+2] cycloaddition of a ketone with anynolate, followed by a Dieckmann condensation to give a 3-lactone as 4-190 which is decarboxylated under reflux in toluene in the presence of silica gel to afford cyclopentenones [64a]. Thus, the reaction of 4-188 and 4-189 led to 4-190, which on heating furnished the linear cucumin 4-191 (Scheme 4.41). This natural product has been isolated from the mycelial cultures of the agaric Macrocystidia cucumis [65, 66]. The domino procedure described was also used to synthesize dihydrojasmone and a-cuparenone. Moreover, the [2+2] cycloaddition can be combined with a Michael reaction [64b]. 

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