Oxo-Michael addition, intramolecular

Roush WR, Hall SE (1981) Studies on the total synthesis of chlorothricol-ide stereochemical aspects of the intramolecular Diels-Alder reactions of methyl undeca-2,8,10-trienoates. J Am Chem Soc 103 5200-5211 Rudler H, Denise B, Xu Y, Parlier A, Vaissermann J (2005) Bis(trimethylsilyl)-ketene acetals as C,0-dinucleophiles one-pot formation of polycyclic y-and 8-lactones from pyridines and pyrazines. Eur J Org Chem 3724-2744 Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise synthesis of anti-HIV-1 Active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-michael addition. J Org Chem 69 2760-2767... 

Using ( )-Quinine Catalyzed Intramolecular oxo-Michael Addition ... 

Ishikawa et al. reported that ( )-quinine-catalyzed asymmetric intramolecular oxo-Michael addition (IMA) of 7-hydroxy-8-tigloylcoumarin gave cis-2,3-dimethyl-4-chromanone systems with high enantioselectivity and moderate diaster-eoselectivity, especially when chlorobenzene was used as a solvent. " Therefore, total synthesis of (+)-calanolide A (1) was achieved by application of the (—)-quinine-catalyzed asymmetric IMA. However, the synthetic route starting from 1,3,5- trimethoxybenzene was too long (13 steps with 3.5% overall yield) to practice. Finally, the authors improved and shortened the original synthetic route by application of Mgl2-assisted demethylation. 

Sekino, E. Kumamoto, T. Tanaka, T. Ikeda, T. Ishikawa, T. Concise synthesis of anti-HIV-1 active (-l-)-inophyllum B and (-l-)-calanolide A by application of (—)-quinine-catalyzed intramolecular oxo-Michael addition. J. Org. Chem., 2004, 69 2760-2769. 

Quite recently, the use of natural cinchona alkaloids as catalysts for the intramolecular oxo-Michael addition of o-tigloylphenol (3), furnishing chiral ris-2,3-dimethyl-4-chromanone 4, which is a valuable intermediate for the synthesis of the anti-HIV-1 active coumarins, (+ )-calanolide A (5a), and (+ )-inophyllum B (5b), was reexamined by Ishikawa and coworkers (Scheme 9.2) [2], The parent cinchona alkaloids,... 

Scheme 15.25 S cnthesis of some anti-HIV-1 active drugs by quinine-catalysed intramolecular oxo-Michael addition.

Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise Synthesis of Anti-HIV-1 Active (+)-Inophyllum B and (-t)-Calanolide A by Application of (-)-Quinine-Catalyzed Intramolecular Oxo-Michael Addition. J Org Chem 69 2760... 

Aroylvinylarylaldehydes (108, Ar = furyl, thiophenyl or pyridyl) react with nitrosoarenes to give heterocyclic ring-fused 1,2-oxazinones (109), using NHC catalysis. Intermediate formation of A-hydroxylamides followed by intramolecular oxo-Michael addition is discussed. 

Alkaloid 1 also catalyzed the asymmetric intramolecular oxo-Michael addition of o-tigloylphenol in chlorobenzene, leading to ctx-2,3-dimethyl-4-chromanone (Scheme 6.3) [18], a valuable intermediate in the total synthesis of (+)-calanoUde A and (+)-inophyllum B. 

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... 

A broad range of enantiomericaUy pure 4,5-dihydrobenzo[r [l,3]diox-epines 177 have been prepared via a four-component Mannich reaction and subsequent intramolecular oxo-Michael reaction (14CC2196). The reactions proceeded with both high enantio- and diasteroselectivity, utilizing a dual catalytic system of Rh2(OAc)4 and a chiral phosphoric acid 178. The rhodium catalyst forms the protic oxonium ylide 174 from a diazo compound 171 and this subsequently adds to imine 175, formed in situ. The resulting enantiomericaUy enriched intermediate 176 then undergoes an intramolecular and diastereoselective oxo-Michael addition to form the final product 177. 

The intramolecular Michael addition of acyclic systems is often hampered by competing reactions, i.e., aldol condensations. With the proper choice of Michael donor and acceptor, the intramolecular addition provides a route to tram-substituted cyclopentanones, and cyclopentane and cyclohexane derivatives. Representative examples are the cyclizations of /3-oxo ester substituted enones and a,/J-unsaturated esters. 

Finally, intramolecular Michael addition from a 3-(2-oxo-but-3-enyl)-oxazolidin-5-one was reported to be catalyzed by boron trifluoride and afforded the cyclized product in fair yields. However, substitution at the enone group resulted in a less efficient cyclization <1996TL14757>. 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

The synthesis of unnatural (+)-mesembrine (387) through the asymmetric synthesis of methyl (i )-l-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390) by cycloaddition of enantiomerically pure vinyl sulfoxide with dichloroketene has been performed 189) (Scheme 43). Vinyl sulfoxide 388 [prepared by conjugate addition of enantiopure acetylenic sulfoxide with (3,4-dimethoxy)phenylcopper] reacted with trichloroacetyl chloride in the presence of freshly prepared zinc-copper couple in THF at 0°C to produce a mixture of mono- and dichloro lactones 389. Reduction of 389 with zinc in acetic acid followed by cyclization and methylation afforded methyl IR-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390), treatment of which with methylamine brought about amidation and concomitant intramolecular Michael addition to provide 2-oxo-mesembrine (391). Successively, 391 was transformed to (+)-mesembrine (387) in 79% yield (three steps ketalization of an oxo group, reduction of lactam, and deketali-zation)(/S9). 

There is also an example of a one-pot reaction in which an initial Michael addition of a functionalized aldehyde containing an olefin moiety at the convenient position to a nitroalkene as Michael acceptor was followed by the formation of a 1,3-dipole and a subsequent intramolecular [3 + 2] cycloaddition (Scheme 7.12). In this case, ethyl 7-oxo-2-heptenoate was reacted with a series of nitroalkenes using 31a as catalyst and next A -hydroxylphenylamine was added to the reaction mixture, promoting the formation of the corresponding... 

Later on, the same group developed another three-component reaction of diazo compounds with anilines and 4-oxo-enolates based on their previous work [44], By controlling the addition sequence of the substrates, this three-component reaction could proceed through an aza-Michael addition/ylide generation/intramolecular aldol... 

The first enantioselective organocatalytic oxo-Michael reaction to enones was reported by Falck [109]. Falck developed the intramolecular addition of boronic acids hemiesters to enones catalyzed by thiourea catalysts. Alkyl, aryl, and heteroaryl y-hydroxy enones react with phenylboronic acid to furnish the corresponding boronic hemiesters 118, which after oxidative cleavage of the resulting dioxaboro-lane renders the chiral 1,2 diols 119 in excellent yields and enantioselectivities (Scheme 33.34). 

SCHEME 53. Microwave-assisted diastereoselective synthesis of a a-spiro-8-lactone via a WoUf rearrangement/a-oxo ketene trapping/cross-metathesis/intramolecular Michael addition consecutive sequence. 

Michael addition of ethyl [3- C]acetoacetate to ethyl crotonate followed by an intramolecular tandem enolate acylation opens an altemative approach to highly substituted labeled resorcinols (e.g., 3291 (see also Section 6.5.1). Aromatization of the initially formed ethyl 6-methyl-4-hydroxy-2-oxo[l- " C]cyclohex-3-ene-l-carboxylate 13271 is readily... 

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