Oxa-Michael cyclization

Phenols have been condensed with alkenoylesters to give chromans by an oxa-Michael addition/electrophilic aromatic addition sequence with magnesium(II)- or copper(II)-bis-oxazoline complexes as chiral Lewis acid catalysts (Scheme 17b) [97]. This reaction may be initiated by an oxa-Michael reaction, followed by a hydroarylation of a carbonyl group. The authors suggest that the initial stereodetermining oxa-Michael addition is followed by a fast diastereoselective aromatic substimtion [97]. A nickel Lewis acid, derived from Ni(hfacac)2 (hfacac = 1,LL5,5,5-hexafluoro-3,5-dioxopentane enolate) and chiral Al-oxide ligands, catalyzes the enantioselective oxa-Michael cyclization of 2-tert-butyloxycarbonyl-2 -hydroxy-chalcones to 3-ferf-butoxycarbonyl flavanones, which can be decarboxylated to flavanons in a separate step (Scheme 17c) [98]. A Lewis acid activation of the unsaturated p-ketoester unit can be assumed. 

The total synthesis of the natural chromone pestalotiopsone A includes a microwave-promoted aldol condensation and oxa-Michael cyclization to construct the chromanone core, followed by 2-iodoxybenzoic acid (IBX)-induced dehydrogenation to afford the desired chromone. The synthesis of pestalotiopsones B, C, and F is also accomplished using similar approaches (13OBC1109). 1,3,5-Trimethoxybenzene is the starting material for the... 

Oxygen nucleophiles Intramolecular oxa-Michael cyclization of a,/ -unsaturated carbonyl compounds (278) (e.g. thioesters, oxazolidinone imides, and pyrrole amides), catalysed by Brpnsted acids, such as camphorsulfonic acid (CSA), has been reported to afford 2,6-cis-substituted tetrahydropyrans (279) with good to excellent stereoselectivity (7 1 to >20 1 dr). The approach has been claimed to be superior to that mediated by bases and is complementary to the ruthenium-catalysed cyclization affording anal- 0 ogous products (149) discussed earlier. 

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). 

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)... 

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 and coworkers used a three-step HWE/oxa-Michael/acid-catalyzed cyclization sequence to access the simplified spirocyclic core 243. Unfortunately, application of this method to a more complex substrate in order to obtain the substituted tetrahydrofuran was tmsuccessful [130]. However, Furstner and coworkers were able to effect a similar cascade from enone 244 in one step, affording tetracyclic spiroacetal 245 in excellent yield as a single isomer. 

In a related example, reaction of N-hydroxy-N-methylthiophene-2-carboximidamide 56 with DMAD gave a double Michael addition product 57, which when heated at reflux in xylenes, afforded hydroxypyrimidinone 60 in 57% overall yield (Scheme 6.21) [9f]. The mechanism invoked was opening of the oxa-diazole 57 to 58, followed by a [3,3]-Claisen-type rearrangement to 59, which, after tautomerization and cyclization, afforded 60. 

The l,3,3,3a,8a-tetrahydro-8-oxa-2-thia- 205, l,3,3,3a,8a-tetrahydro-2,8-dioxa- 206, and 3,3a,8,8a-tetrahydro-12/-2-thia-8-aza-cyclopenta[ ]indene-2,2-dioxide 207 were prepared by Michael addition or radical cyclization from the corresponding sulfones 202-204 and brominated-dehydrobrominated (in the case of 207, after tosylation) to produce 1,5-diheteropentalene systems 208-210, respectively <1997TL5315>. 

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