Keto groups, addition

Keto-l,3-en-2-ols s. Tropolones Keto groups, addition of acylamino groups to —... 

The synthesis of spiro compounds from ketones and methoxyethynyl propenyl ketone exemplifies some regioselectivities of the Michael addition. The electrophilic triple bond is attacked first, next comes the 1-propenyl group. The conjugated keto group is usually least reactive. The ethynyl starting material has been obtained from the addition of the methoxyethynyl anion to the carbonyl group of crotonaldehyde (G. Stork, 1962 B, 1964A). 

AHylestrenol (37) is prepared from (32), an intermediate in the synthesis of norethindrone. Treatment of (32) with ethanedithiol and catalytic boron trifluoride provides a thioketal. Reduction with sodium in Hquid ammonia results in the desired reductive elimination of the thioketal along with reduction of the 17-keto group. Oxidation of this alcohol with chromic acid in acetone followed by addition of aHyl magnesium bromide, completes the synthesis... 

Lynestrenol is the des-3-oxo derivative of norethindrone (28). It has been prepared through a similar synthetic pathway as aHylestrenol (37) (52), ie, addition of potassium acetyUde, rather than aHyl magnesium bromide, affords lynestrenol (73). Lynestrenol is also available from norethindrone (28). Reduction of the 3-keto group is accompHshed by treating norethindrone (28) with sodium borohydride in the presence of trifluoro- or trichloroacetic acid... 

The reaction of 9(1 l)-dehydro steroids with nitrosyl fluoride was studied by Grantz and Rosenthal in pursuit of an alternate source for the important 9a-fluoro-11-oxygenated steroids. As expected, reaction at the more hindered 9(1 l)-double bond proceeds more slowly than at either the 4- or 5-double bonds. After 10 days at 3°, 3 -acetoxy-5a-pregn-9(l l)-en-20-one (50) affords a 45% yield of the 9a-fluoro-ll-nitrimine (51). Other 9a-fluoro-ll-nitrimines were prepared and it was found that the presence of additional keto groups, particularly the 3-keto group gives rise to side products with a concomitant reduction in yield of the desired 9a-fluoro-ll-nitrimines. In the case of the A" -3-ketones the yield is reduced to 10 %. The steric hindrance... 

The 11-keto group is relatively difficult to attack, due to steric hindrance. However, reaction of 3j -hydroxy-5a-androstane-l 1,17-dione (37) with methylmagnesium bromide at 25° unexpectedly gives a 30% yield of 1 la,17a-dimethyl-5a-androstane-3j5,lljS,17i -triol (38) in addition to the 17-monomethyl product (39). 

The addition of diazomethane to 17j -hydroxy-5a-androst-l-en-3-one (7) gives the A -pyrazoline (8) in which the C=N bond is conjugated with the 3-keto group. °°... 

Reaction of tryptamine with simple ketones has not been widely explored. Acetone in the presence of benzoyl chloride has been reported to yield 2-benzoyl-1,1 -dimethyl-1,2,3,4-tetrahydro-j8-carbo-line. That the keto group is much less reactive than the aldehyde group is indicated by the fact that j8-keto aldehydes, in the form of their acetals or sodium salts, react with tryptamine at the aldehyde function to yield the conjugated enamine 24, which undergoes ring closure via an intramolecular Michael addition. The potentialities of this interesting modification of the Pictet-Spengler reaction have not yet been fuUy explored. 

A slightly more complex anti arrhythmic agent is pi rmentol (74). It is synthesized from 4-chloropropiophenone (72) by keto group protection as the dioxolane (with ethylene glycol and acid) followed by sodium iodide-mediated alkylation with cis 2,6-dimethyl pi peri dine to give 7. Deblocking with acid followed by addition of 2-1ithiopyridine completes the synthesis of pi rmentol (74). 

Q Nucleophilic addition of coenzyme A to the keto group occurs, followed by a retro-Claisen condensation reaction. The products are acetyl CoA and a chain-shortened fatty acyl CoA. 

The retro-Claisen reaction occurs by initial nucleophilic addition of a cysteine -SH group on the enzyme to the keto group of the /3-ketoacyl CoA to yield an alkoxide ion intermediate. Cleavage of the C2-C3 bond then follows, with expulsion of an acetyl CoA enolate ion. Protonation of the enolate ion gives acetyl CoA, and the enzyme-bound acyl group undergoes nucleophilic acyl substitution by reaction with a molecule of coenzyme A. The chain-shortened acyl CoA that results then enters another round of tire /3-oxidation pathway for further degradation. 

A useful method to synthesize ten and fourteen-membered ring imides 346 involved an initial condensation of macrocyclic -ketoestes 343 with alkyl or aryl isocyanates and carbodiimides, respectively, in the presence of a base [68]. After a nucleophilic attack of the enolate on the isocyanate C, the resultant amide N anion 344 induced a ring closure by addition to the keto group. Then, the intermediately formed four-membered ring 345 underwent a fragmentation... 

In a typical example of aliphatic cyclizations, already discussed in Section 5.2, the enamine 675 is alkylated by silylated methyl 4-chloroacetoacetate 747 a [2] to give, via 760 and subsequent ehmination of pyrrolidine, the unsaturated bicycHc /9-ke-toester 761 in, as yet, only 30-40% yield [1]. Analogously, the bicycHc system 1408 with an additional 6-keto group is silylated to 1409 and cyclized via 1410, in an overall yield of 42%, to the tricyclic capnellene intermediate 1411 [3] (Scheme 9.1). An alternative synthesis of bicyclic compounds Hke 761 is given elsewhere [3 a]. 

Comparison of the compression and expansion cycles for C-15 6,6 diacids linked with a carbonyl group (Fig. 41) and those linked with an amide group (Fig. 51A) show that the C-15 amide diacids, 6-(6-pentadecanoiccarbamoyl)-pentadecanoic acids (C-15 6,6 -A), also form much more highly condensed monolayers than do their keto counterparts. Addition of three methylene... 

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