Intramolecular oxa-Michael addition

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... 

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]. 

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... 

Sun and coworkers established an alternative diastereoselective approach to 3-amino-l-indanols that proceeds under mild conditions. They employed chalcone-derived aldehydes 71 and treated them with weak nitrogen nucleophiles and catalytic amounts of base (Scheme 8.20) [34]. Electron-rich and -deficient substrates as well as several amines were tolerated and gave rise to 72 in very good yields and diastereoselectivities up to >30 1. Sulfonamides were shown to be the best choice with respect to their abihty to add to the a,P-unsaturated ketone. The generated enolate subsequently attacked the aldehyde in an intramolecular aldol reaction. The alternative reaction pathway involving an initial aldehyde attack followed by an intramolecular oxa-Michael addition could be suppressed by using DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) as the appropriate base. 

In 2008, the group of Williams [15] reported the first total synthesis of ( )-2-0-methylneovibsanin H (33) (Scheme 14.6). The diterpene, isolated from the leaves of Viburnum awabuki [16], was prepared by employing an acid-catalyzed domino sequence. Thus, the key transformation was the conversion of advanced intermediate 28 to cyclohexene 32 upon treatment with an excess of sulfuric acid in anhydrous methanol. Acid-mediated silyl deprotection first revealed alcohol 29, which readily underwent an intramolecular oxa-Michael addition to yield tricyclic 30. It was postulated that solvolysis and nucleophilic addition of methanol to the intermediary allyl cation then furnished acid 31, which underwent Fischer esterification. The resultant highly functionalized cyclohexene 32 was isolated in 50% yield as a mixture of diastereomers at C2 (diastereomeric ratio (dr) = 85 15). The observed stereochemistry at the newly created stereocenters, i.e., at C2 and C5, was postulated to arise from the preexisting sterically congested stereocenters in the starting material (i.e., 28). Cyclohexene 32 was eventually taken on to provide the natural... 

The substrate reactivity problem was solved by developing an intramolecular oxa-Michael addition/decarbo>ylation tandem reaction of allq lidene p-ketoesters catalysed by modified Cinchona alkaloids.By using 0-benzylcupreidine (O-Bn-CPD) as catalyst, a series of chiral flavanone derivatives have been prepared with high enantioselectivities (up to 93% ee) and excellent yields (Scheme 15.26). 

Zhao reported the organocatalytic asymmetric synthesis of fluorinated flavanone derivatives by a tandem intramolecular oxa-Michael addition/ electrophilic fluorination and among various Cinchona alkaloid catalysts screened, the best results were obtained using cupreidine substituted with (4-CF3)-benzyl at the 9-0 position. ... 

The synthesis of unique seven-membered ring sultams has been reported, by an intramolecular oxa-Michael addition reaction from vinyl sulfonamides 248 via a one-step or two-step method, both of which give similar yields of sultams, 249 (13T2369).The intramolecular oxa-Michael reaction was initiated by either TBS-deprotection (with TBAF) to form alkoxide intermediates (Method A), or by removal of the protecting group by HCl to give vinyl sulfonamide alcohols which, upon reaction with NaH, the oxa-Michael reaction is initiated (Method B). 

Intramolecular oxa-Michael addition of activated enones with an in situ generated JVjiV -dioxide nickel catalyst. 

After the failure of the intramolecular 8 2 attack strategy, intramolecular oxa-Michael strategy was used to test the seven-membered ring formation. The retro-synthetic analysis is shown in Fig. 3.21. Key intermediate 3.38 was inversed to its analog 3.46 while compound 3.46 could be synthesized from compound 3.47 through an intramolecular oxa-Michael addition reaction. 

This Pt-catalyzed hydroarylation was further applied to the total synthesis of deguelin 117, a rotenoid with promising chemopreventive properties (Scheme 12.51) [55]. Although PtCl proved to be superior to PtCl2 as catalyst in model systems for the 6-endo hydroarylation of alkynones and alkynoates, the cyclization of 115 with PtCl led only to poor yields of 116. However, the reaction of 115 with PtCl2 as catalyst provided 116 in excellent yield. The synthesis of racemic deguelin 117 was completed by selective demethylation with boron trichloride, followed by a base-catalyzed intramolecular oxa-Michael addition. 

Brimble et al. [127] for the synthesis of bis(benzannulated)-spiroacetals 238 (Scheme 58). Deprotection of the EOM group in chromones 236 prompted intramolecular oxa-Michael addition of the resulting phenol in most cases. In the two examples where only the free phenol 237 was recovered, the spirocyclization could be induced by heating the neat phenol with dry potassium carbonate under micro-wave irradiation. The resulting bis(benzannulated) 6,6-spiroacetals were obtained in low to moderate yields. 

Wang H-F, Cui H-F, Chai Z, Li P, Zheng C-W, Yang Y-Q, Zhao G. Asymmetric synthesis of fluorinated flavanone derivatives by an organocatalytic tandem intramolecular oxa-Michael addition/electrophilic fluorination reaction by using bifunctional cinchona alkaloids. Chem. Eur. J. 2009 13299 13303. 

Olefin cross-metathesis followed by intramolecular oxa-Michael addition, catalysed by the second-generation Hoveyda-Gmbbs catalyst, has been developed as a cascade, one-pot procedure for 5-hydroxy olefins (147) and a,/ -unsaturated carbonyl compounds (148) (trani-crotonaldehyde or A-acryloyl-2,5-dimethylpyrrole, etc.) as the reacting partners. In the presence of a Brpnsted acid in CH2CI2 at 25-35 °C, the resulting 2,6-cA-substituted tetrahydropyrans (149) were obtained with excellent diastereoselectivity. The role of ruthenium hydride intermediates has been investigated in detail. 

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