Unsaturated ketones cyclic, synthesis

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

As an extension of this work, the same authors explored such methodology for the synthesis of 2,6-disubstituted dihydropyrans using secondary homopropargylic alcohols (Scheme 10, route E). Surprisingly, the treatment of pent-4-yn-2-ol and 3-methylbutanal in the presence of FeCls led to unsaturated ( )-(3-hydroxyketone and ( )-a,p-unsaturated ketone in 2.5 1 ratio and 65% yield, without any trace of the expected Prins-type cyclic product (Scheme 22) [36]. To test the anion influence in this coupling, FeCE and FeBrs were used in a comparative study for the reaction of pent-4-yn-2-ol (R = R" = H, = Me) and several aldehydes. A range of aldehydes except for benzaldehyde was transformed into unsaturated (3-hydroxy-ketones in moderate to good yields. 

Asymmetric reduction of a,fi-enon s. This combination of reagents (1 1) in conjunction with N-cthylaniline (2 equivalents) reduces alkyl aryl ketones to alcohols with high stereoselectivity.1 Under these conditions 2,/1-unsaturated ketones arc reduced to optically active (S)-allylic alcohols. Optical yields of 80 98% have been reported for open-chain enones. Reduction of cyclic enones is somewhat less efficient. The method was used to reduce 1 to 2, which has been used as an intermediate in an anthracyclinone synthesis.2... 

Cyclic ketones react with unsaturated ketones to form fused pyrylium salts (667) (58JCS1978), whilst the use of phenylacetaldehyde allows the synthesis of pyrylium salts unsubstituted at C-6 to be achieved (65BSF1944). 

The third type is common to monoepoxides of cyclic 1,3-dienes In five- to eight-membered rings and results in rearrangement to /3,y-unsaturated ketones in 55-80% yield. This isomerization can be utilized as one step in a route to 4-hydroxy-2-cycloenones. An example is a synthesis of 4-hydroxy-2-cyclopentenone formulated in equation (III). 

A chiral complex of (1), L1A1H4, and A/-ethylaniline (molar ratio, 1 1 2) reduces aryl alkyl ketones to optically active alcohols in high ee. a, -Unsaturated ketones are reduced enantioselectively to afford optically active (S)-allylic alcohols with 80-98% ee. An intermediate in an anthracyclinone synthesis is prepared in 92% ee by the enantioselective reduction of a cyclic a,p-unsaturated ketone (eq 2). ... 

A study of the photoreduction of the oxoamides (103) in acetonitrile/triethylamine has shown that the oxoamides (103 a,b) afford the alcohols (104) in high yield. However, the amides (103 c,d) and (105) are also reactive and afford the cyclized compounds (106 - 108) respectively. The failure of the oxoamides (103 a,b) to undergo cyclization is presumed to be due to intramolecular hydrogen bonding. The ease with which this reductive cyclization occurs with amides or unsaturated ketones has been exploited in a new synthesis of hirsutene (109). Thus irradiation (254 nm) of the ketone (110) in acetonitrile/triethylamine affords the alcohol (111, 20X) and the desired cyclic compound (112, S8X). This latter material is readily converted to hirsutene. The ketone... 

Several years later Danishefsky introduced l-methoxy-3-trimethylsilyloxy-l,3-butadiene, a highly reactive diene, which upon reaction with (not activated) aldehydes catalyzed with mild Lewis acids [(Eu(fod)3] afforded cyclic a, -unsaturated ketones [19]. Another method involved reaction of l,4-di-alkoxy(acyloxy)-butadiene with an activated heterodienophile, which led to more functionalized derivatives (Schmidt) [20]. This methodology may be illustrated by the classical synthesis of the precursor of purpurosamine B (3) and higher sugar... 

The total synthesis of galbulimima alkaloid GB 13 was accomplished by L.N. Mander and co-workers. The Birch reduction of a complex intermediate was necessary in order to prepare a cyclic a,p-unsaturated ketone. The treatment of the substrate with lithium metal in liquid ammonia first resulted in a quantitative reductive decyanation of the C6a cyano group. The addition of excess ethanol to the reaction mixture reduced the aromatic ring to the corresponding enol ether that was hydrolyzed in a subsequent step to afford the unsaturated ketone. 

Fujimoto-Belleau reaction. Synthesis of cyclic a-substituted a,(3-unsaturated ketones from enol lactones and Grignard reagents prepared from primary halides. 

The Corey-Bakshi-Shibata reduction (CBS reduction) is a highly enantioselective method for arylketones, diaryl ketones, and dialkylketones. In addition, cyclic a,p-unsaturated ketones, acyclic a,p-unsaturated ketones, and a,p-ynones are reduced enantioselectively in a 1,2-fashion. The high enantioselective nature of this reduction relies on the chiral oxazaborolidine catalyst, shown in the reaction scheme, in the presence of borane or a dialkylborane. Reviews (a) Singh, V. K. Synthesis 1992, 605-617. (b) Deloux, L. Srebnik M. Chem. Rev. 1993,93,163-1. (c) Corey, E. J. Helal, C. J. Angew. Chem. Int. Ed. 1998, 37. 1986-2012. 

The cyclic unsaturated ketone (48) has been used in a synthesis of bullatenone (47) (see Chapter 20 and workbook for Chapter 20) and as a dienophile in Diels-Alder reactions. Disconnection of the enol ether reveals both 1,2- and 1,3-relationships in (49) and one of the 1,3-disconnections... 

The use of the carbanion derived from the chloroallylphosphonate (163) in the enantioselective synthesis of cyclopropanes (164) by Michael addition to a,P-unsaturated ketones has been the subject of a short review (Scheme 18). Denmark s group have published full details of the asymmetric Michael addition reactions of cyclic enones with carbanions derived from l,3,2-oxa2aphosphor-inane 2-oxides (165) and (167). y-Addition to give (166) predominates although the extent of this depends on the ring size of the Michael acceptor. The level of diastereoselectivity depends on the stereochemistry of the allylphosphonate used ... 

Pyranopyridines have been obtained by a one-pot reaction of 10 and unsaturated ketones. Benzopyranopyridines 109 have been prepared from isoquinolinediones 108. Another synthesis was performed by condensation of an u-hydroxyaraldehyde with a cyclic methyl ketone followed by treatment with 10. Pyranobenzodiazepines 111 have been obtained by condensation of 10 with benzodiazepinones 110 4-Dicyanomethylene-l,3-benzoxazines 113 were formed by treating dithiazolidine derivatives 112 with 10. ... 

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