Intramolecular oxa-Michael

Scheme 7.74 Epoxidation of enones by cascade oxa-Michael/intramolecular nucleophilic displacement.

Since heterocycles containing a trifluoromethyl group are representatives of a major structure type in agricultural and medicinal chemistry, Shibata ct al. have developed a novel enantioselective synthesis of trifluoromethyl-substituted 2-isoxazolines 46 on the basis of a domino oxa-Michael-intramolecular hemi-aminahzation-dehydration reaction of hydroxylamine with a range of ( )-trifluoromethylated enone derivatives 47 [81]. This process, which employed N-3,5-bis(trifluoromethyl)benzyl-quinidinium bromide 48 as a chiral phase-transfer catalyst combined with CsOH as a base provided a series of trifluoromethyl-substituted 2-isoxazolines 46 in high yields and enantioselectivities of up to 94% ee (Scheme 37.8). 

Scheme 37.8 Synthesis of trifluoromethyl-substituted 2-isoxazolines through a domino oxa-Michael-intramolecular hemi-aminalization-dehydration reaction.

Transformation of the 7-oxo-2-enimides 28, available from chiral syn-aldols by a Cope rearrangement, into enantiopure tetrahydropyrans involves reduction of the aldehyde function followed by a fast intramolecular oxa Michael addition. The stereochemical course of the... 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

The Bu OK-promoted reaction of 4-chlorobut-2-yn-l-ol (11) with nitroalkenes (12) gives 3-vinylidenetetrahydrofurans (14) in good yields with complete dia-stereoselectivity.12 It is supposed that oxa-Michael addition to fonn the intermediate (13) is followed by intramolecular 5k 2 substitution. 

Polyhaloalkyl-substituted chromones and 7-pyrones react with salicylaldehydes in the presence of piperidine to give a variety of fused 277-chromenes in good yields (Scheme 58) <2006JOC4538>. Although it is conceivable that this reaction could proceed through a Baylis-Hillman reaction pathway, studies of this reaction point to the mechanism being a tandem intramolecular oxa-Michael addition and subsequent Mannich condensation. 

A 2,2-disubstituted chromane system was asymmetrically constructed by application of intramolecular oxa-Michael addition reaction through 6-exo-trig mode cyclization [57]. Good asymmetric induction at the quaternary carbon was observed when Z-alkene was treated with the same guanidine 17 used in asymmetric carba-Michael reaction in Table 4.5 (Scheme 4.18). 

Scheme 4.18 Guaniodine catalysed intramolecular oxa-Michael addition...

Saito, N., Ryoda, A., Nakanishi,W. eta/. (2008) Guanidine-catalysed asymmetric synthesis of 2,2-disubstituted chroman skeletons by intramolecular oxa-Michael addition. European Journal of Organic Chemistry, 2759-2766. 

Gold A gold-catalyzed oxa-Michael addition has been discussed as one step in a multi-step sequence involving aUcyne hydration, p-elimination of methanol, and intramolecular oxa-Michael addition [87, 88]. 

Scheme 4.62 Enantioselective intramolecular oxa-Michael reactions for the synthesis of chromanes.

There is also an interesting example of an enantioselective thiourea-catalyzed oxa-Michael reaction using enones as Michael acceptors in which phe-nylboronic acid was employed as hydroxyl anion equivalent (Scheme 4.64) The authors demonstrated that amine bases were able to activate these kinds of reagents by complexation, thus becoming effective reagents for the transfer of the OH group to the Michael acceptor. The reaction had to proceed in an intramolecular way and, for this reason, y-hydroxy-a,(3-unsaturated ketones had to be employed as substrates. In the enantioselective version, 71b was identified as a very efficient catalyst, providing a series of (3,y-dihydroxy ketones in excellent yields and enantioselectivities, after oxidative work-up. The process consists of the initial reaction of the boronic add first with the y-hydroxy... 

Scheme 4.63 Enantioselective intramolecular oxa-Michael reaction for the synthesis of chromanones and flavanones.

Enantioselective synthesis of N-protected aminodiols 235 and 239 via dia-stereoselective inter- and intramolecular cycloaddition of optically active nitrile oxides 233 and 237 followed by cleavage of the isoxazoHnes 234 and 238 has been reported by Enders and co-workers (Schemes 55 and 56) [156]. The nitrile oxides 233 and 237 were generated from nitroalkanes 232 and 236, respectively, which in turn were obtained by diastereoselective oxa-Michael addition of (IR, 2S)-(-)-N-formylnorephedrine 231 to ahphatic nitroalkenes 75b,c. The LiAIH4-mediated cleavage of isoxazolines 234 and 238 to aminoal-cohols 235 and 239, respectively, proceeded with >96% diastereoselectivity. 

The synthesis of the as-fused butyrolactone tetrahydropyran core of (-b)-Greek tobacco lactone involves an intramolecular oxa-Michael reaction of a furan-3-en-2-one bearing a propanediol chain at C-5 (14SL1888). Prins cyclization of ( /Z)-6-mercaptohex-3-en-l-ol with aliphatic and aromatic aldehydes is condition-controlled stoichiometric amounts of strong Lewis or Bronsted acids afford mainly thiophen[c]-fused tetrahydropyrans whereas catalytic amounts of weak Lewis or Bronsted acids provide furan[c]-fiised tetrahydrothiopyrans as major products (Scheme 13)... 

High yields of 2-substituted chromans are readily attained from the asymmetric intramolecular oxa-Michael addition reaction of phenols bearing an (f -a,P-unsaturated ketone or thioester moiety mediated by a cinchona-alkaloid-urea-based bifunctional organocatalyst (140BC119). Molecular iodine-catalyzed reaction of phenols with a,P-unsaturated alcohols affords a wide range of 2,2-disubstituted chromans (14T5221). Chiral derivatives result from the intramolecular allylic alkylation of phenols bearing an... 

Intramolecular oxa-Michael reaction of 2 -hydroxychalcones promoted by an organocatalyst based on aminoquinoline and pyrrolidine leads to 2-aryl-4ff-chroman-4-ones, in good yields with high enantioselectivity (14TL3255). A wide range of 3-aryl-4H-chroman-4-ones are readily... 

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

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