Angular alkylation

Classical syntheses of steroids consist of the stepwise formation of the four rings with or without angular alkyl groups and the final construction of the C-17 side-chain. The most common reactions have been described in chapter 1, e.g. Diels-AIder (p. 85) and Michael additions (p. 

Application of the reductive alkylation process to the -20-ketone (4) yields the 17a-alkyl derivatives (5a-c). As expected, the presence of the angular 13-methyl group favors the approach of the alkyl iodide from the a-side. ... 

Amino-2,l,3-benzothiadiazole treated under similar conditions afforded, re-gioselectively, an analogous angularly annelated ester 68 and acid 69, both to be tested for inhibition of the DNA synthesis (74MI1). Subsequent alkylation of the... 

Ab initio calculations on aza-Diels-Alder reactions of electron-deficient imines with buta-l,3-diene show that these reactions are HOMO (diene)-LUMO(dienophile)-controlled and that electron-deficient imines should be more reactive than alkyl-or aryl-imines. The Diels-Alder reaction of r-butyl 2//-azirine-3-carboxylate (80) proceeds with high diastereoselectivity with electron-rich dienes (81) (Scheme 28). The hetero-Diels-Alder additions of imines with sterically demanding dienes yield perhydroquinolines bearing an angular methyl group. The asymmetric hetero-Diels-Alder reaction between alkenyloxazolines and isocyanates produces diastereometri-cally pure oxazolo[3,2-c]pyrimidines. °... 

XLIV) centers about elaboration of hydroxymethylene ketone (574) into the tricyclic diketone (578). Alkylation of keto nitrile 575 proceeds exclusively cis to the angular methyl groups as does the subsequent reductive methylation. These authors were not able to achieve aldol cycUzation of keto aldehyde 576 and consequently proceeded to enol lactone 577 The addition of a methyl group to 578 could be achieved regioselectively. Subsequently dehydration gave 579 and its endocyclic isomer which were separated chromatographically. 

Interest in the total synthesis of the Aspergillus terreus derived quadrone fi06), an antitumor agent has been very intense. Success was first realized in Danishefsky s laboratory Once 601 was reached, its sidechain was elaborated and ring closure effected (Scheme LII). Condensation of 602 with 1-tert-butoxy-l-tcrt-butyl-dimethylsiloxyethylene in the presence of titanium tetrachloride and subsequent desilylation resulted in introduction of an angular acetic acid moiety. The two sidechains were next connected by intramolecular alkylation and the resulting keto add was subjected to selenenylation in order to produce 603. The a, P-unsaturated double bond was used to force enolization to the a position. Indeed, 604 was... 

Alkylations of tran.v-2-decalone enolates 30 have been performed with high degrees of diastereose-lectivity. 1,3-Interactions are clearly very important steric-control elements in the angularly substituted compounds. The examples shown also demonstrate that reductive alkylations of a,/ -unsaturated ketones are a useful diastereoseleclive step in the syntheses of polycyclic compounds19 11 7S-80. 

Angular alkylations of fused-ring ketones are an important step in syntheses of terpenoids, steroids and related natural products. The steric course of these alkylations has therefore been the subject of several systematic investigations and has been reviewedl 3 71. Alkylation of the lithium enolate 38 (R = H) derived from octahydro-1 (2//)-naphthalenone (1 -decalone) primarily yields the civ-fused octahydro-8a-methyl-l(2F/)-naphthalenone (39, R = H)35,62,79. Due to steric reasons, the lithium enolate 38 (R = CH3), with an angular methyl group, provides the irans-fused product 39 (R = CH3). 

The angular alkylations of the lithium enolates 40 and 42, derived from hexahydro-l-indanone and 3a,4,7,7a-tetrahydro-l-indanone, respectively, preferentially provide the tram-fused products60. 

Whereas the reaction of the linearly fused 117/-pyrido[2,l -h]quina-zolin-ll-one (27) with alkylating agents (dimethyl sulfate at 120°C, and tri-ethyloxonium tetrafluoroborate in methylene chloride at 20°C) gave exclusively 7V(5)-alkylated quaternary salts (107), that of the isomeric angularly fused 6//-pyrido[l,2-a]quinazolin-6-one (28) with the soft methyl iodide afforded only the iV(5)-methyl quaternary iodide (108, X = I). The reactions of 28 with the hard dimethyl sulfate and triethyloxonium tetrafluoroborate yielded a mixture of 5-methyl-6-oxo-6//-pyrido[l,2-a]quinazolinium salts (108) and 6-alkoxypyrido[l,2-a]quinazolinium salts (109) (90JHC2005). 

Angular methylation at positions 8a, 9a and 14a has been carried out with the unsaturated keto steroids (16),158,159 (18), (20)160 and (21).161,162 The observed result is due to the presence of the double bond which controls the direction of enolization. Proton abstraction results in the formation of a conjugated dienolate anion which is alkylated from the less hindered side at the most electronegative carbon atom. 

With 0,-y-unsaturated a -diazo ketones, the resulting [2.1.0]-bicyclic systems (40) were quite unstable and underwent a [2 + 2] cycloreversion to generate ketenes (41), which were then trapped by nucleophiles (Scheme 7). The overall scheme has been named a vinylogous Wolff rearrangement and offers a novel entry to products usually derived from a Claisen rearrangement.102 A recent report describes its application for functionalized angular alkylation in fused ring systems.103 In contrast, the intramolecular re-... 

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