1.4-Adducts, lithium

A study of 1,2-versus 1,4-addition to a series of cyclopenten-l-ones bearing a-donor substituents (X = H, Cl, Br, OMe, pyrrolidin-l-yl, SPh, and SePh) at position 2 has established that MeLi gives 1,2-adducts in 28-75% yield and no 1,4-adduct, lithium dimethylcuprate gives only 1,4-addition (51-76%), and cyanomethyl lithium gives mainly 1,2-adducts (43-60%). Theoretical calculations reveal that the predominance of 1,2-attack in the reactions involving MeLi and cyanomethyllithium cannot be explained by the relative thermodynamic stabilities of the products. 

A convenient and general method has been developed for the synthesis of alkylpyrroles starting from ketones and nitroalkenes via reduction of the intermediate acetic nitronic anhydride as shown in Eq. 10.1. Ketone enolates react with a variety of nitroalkenes to yield the Michael adducts, lithium nitronates, which are trapped with acetic anhydride to give the corresponding acetic nitronic anhydrides. The acetic nitronic anhydrides are easily converted into alkylpyrroles by reduction with Zn(Cu).3... 

Acid chlorides Diacetyl-trimethyl phosphite adducts. Lithium nitride. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Iodine azide, on the other hand, forms pure adducts with A -, A - and A -steroids by a mechanism analogous to that proposed for iodine isocyanate additions. Reduction of such adducts can lead to aziridines. However, most reducing agents effect elimination of the elements of iodine azide from the /mwj -diaxial adducts of the A - and A -olefins rather than reduction of the azide function to the iodo amine. Thus, this sequence appears to be of little value for the synthesis of A-, B- or C-ring aziridines. It is worthy to note that based on experience with nonsteroidal systems the application of electrophilic reducing agents such as diborane or lithium aluminum hydride-aluminum chloride may yet prove effective for the desired reduction. Lithium aluminum hydride accomplishes aziridine formation from the A -adducts, Le., 16 -azido-17a-iodoandrostanes (97) in a one-step reaction. The scope of this addition has been considerably enhanced by the recent... 

A convenient route to steroidal aziridines from the diaxial IN3-olefin adducts, e.g., (99), which undergo elimination with lithium aluminum hydride, was developed by Galle and Hassner. Upon treatment with trialkyl phosphite, these adducts are converted to A-phosphorylated aziridines which are reduced by lithium aluminum hydride to the free steroidal aziridine. 

The properties of chlorine azide resemble those of bromine azide. Pon-sold has taken advantage of the stronger carbon-chlorine bond, i.e., the resistance to elimination, in the chloro azide adducts and thus synthesized several steroidal aziridines. 5a-Chloro-6 -azidocholestan-3 -ol (101) can be converted into 5, 6 -iminocholestan-3l -ol (102) in almost quantitative yield with lithium aluminum hydride. It is noteworthy that this aziridine cannot be synthesized by the more general mesyloxyazide route. Addition of chlorine azide to testosterone followed by acetylation gives both a cis- and a trans-2iddMct from which 4/S-chloro-17/S-hydroxy-5a-azidoandrostan-3-one acetate (104) is obtained by fractional crystallization. In this case, sodium borohydride is used for the stereoselective reduction of the 3-ketone... 

Strong acids or superacid systems generate stable fluorinated carbocations [40, 42] Treatment of tetrafluorobenzbarrelene with arenesulfonyl chlorides in nitro-methane-lithium perchlorate yields a crystalline salt with a rearranged benzo barrelene skeleton [43] Ionization of polycyclic adducts of difluorocarbene and derivatives of bornadiene with antimony pentafluonde in fluorosulfonyl chloride yields stable cations [44, 45]... 

A characteristic reaction of sulfmylimines RNSO is the quantitative addition of R Li reagents to form adducts of the type Li[RNS(R )NR]. ° The structures of these sulfmimidinates are discussed in Section 10.4.4." The reactions of RNSO derivatives with two equivalents of lithium tert-butylamide result in the formation of diazasulfite anions [OSNR(N Bu)] (9.12) (Eq. 9.12)." The dilithium derivatives of these dianions form hexameric thirty-six atom (Lii2Ni206S6) clusters with structures that are dependent on the nature of the R group. 

In view of the facile oxidation of 10.13a-c it is not surprising that some metathetical reactions with metal halides result in redox behaviour. Interestingly, lithium halides disrupt the dimeric structures of 10.13a or 10.13c to give distorted cubes of the type 10.14, in which a molecule of the lithium halide is entrapped by a Ei2[E(N Bu)3] monomer. Similar structures are found for the MeEi, EiN3 and EiOCH=CH2 adducts of 10.13a. In the EiN3 adduct, the terminal... 

The in situ generation of the carbon dioxide adduct of an indole provides sufficient protection and activation of an indole for metalation at C-2 with r-butyl-lithium. The lithium reagent can be quenched with an electrophile, and quenching of the reaction with water releases the carbon dioxide. ... 

In the case of 1,3-diphenylisoindole (29), Diels-Alder addition with maleic anhydride is readily reversible, and the position of equilibrium is found to be markedly dependent on the solvent. In ether, for example, the expected adduet (117) is formed in 72% yield, whereas in aeetonitrile solution the adduet is almost completely dissociated to its components. Similarly, the addition product (118) of maleic anhydride and l,3-diphenyl-2-methjdi.soindole is found to be completely dissociated on warming in methanol. The Diels-Alder products (119 and 120) formed by the addition of dimethyl acetylene-dicarboxylate and benzyne respectively to 1,3-diphcnylisoindole, show no tendency to revert to starting materials. An attempt to extrude carbethoxynitrene by thermal and photochemical methods from (121), prepared from the adduct (120) by treatment with butyl-lithium followed by ethyl chloroform ate, was unsuccessful. 

The lithium enolate of the 2(5//)-furanone 58 reacted with aldehydes to give a mixture of the y-adducts 154 and 155 together with the a-adduct 156, typically in a 1 1 6 ratio (Scheme 45) however, no significant selectivity was achieved (87TL985). 

Preparation of cholesta-5,7-diene-ia,3/3-diol a solution of 500 mg of the 1,4-cyclized adduct of cholesta-5,7-dien-3/3-ol-ia,2a-epoxideand 4-phenyl-1,2,4-triazoline-3,5-dione in 40 ml of tetrahydrofuran is added dropwise under agitation to a solution of 600 mg of lithium aluminum hydride in 30 ml of THF. Then, the reaction mixture liquid Is gently refluxed and boiled for 1 hour and cooled, and a saturated aqueous solution of sodium sulfate is added to the reaction mixture to decompose excessive lithium aluminum hydride. The organic solvent layer is separated and dried, and the solvent Is distilled. The residue Is purified by chromatography using a column packed with silica gel. Fractions eluted with ether-hexane (7 3 v/v) are collected, and recrystallization from the methanol gives 400 mg of cholesta-5,7-diene-la, 3/3-diol. 

Still s synthesis of monensin (1) is based on the assembly and union of three advanced, optically active intermediates 2, 7, and 8. It was anticipated that substrate-stereocontrolled processes could secure vicinal stereochemical relationships and that the coupling of the above intermediates would establish remote stereorelationships. Scheme 3 describes Still s synthesis of the left wing of monensin, intermediate 2. This construction commences with an aldol reaction between the (Z) magnesium bromide enolate derived from 2-methyl-2-trimethylsilyloxy-3-pentanone (21) and benzyloxymethyl-protected (/ )-/ -hydroxyisobutyraldehyde (10).2° The use of intermediate 21 in aldol reactions was first reported by Heathcock21 and, in this particular application, a 5 1 mixture of syn aldol diastereoisomers is formed in favor of the desired aldol adduct 22 (85% yield). The action of lithium diisopropylamide (LDA) and magnesium(n) bromide on 21 affords a (Z) magnesium enolate that... 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

Lithium foil is commercially available. Its surface is covered with a "native film" consisting of various lithium compounds [Li0H,Li20,Li3N, (Li20-C02) adduct, or Li2C03], These compounds are produced by the reaction of lithium with 02, H20, C02, or N2. These compounds can be detected by electron spectroscopy for chemical analysis (ESCA) [2], As mentioned below, the surface film is closely related to the cycling efficiency. 

To a solution of 34.6 mmol of lithium 1 -(dimethylamino)naphthalenide34 in THF at — 60°C are added dropwise 3.20 g (15.7 mmol) of l-methylene-2-phcnylthiocyclohexane in 20 mL of THF. The color of the solution changes from dark green to brown when the reagent is consumed yield >90% (estimated from the yield of aldehyde adducts). 

The lithium-TMEDA complex 1, obtained by deprotonation of (S)-(E)-1 -methyl-2-butenyl diisopropylcarbamate (84% ee), affords, after metal exchange by tetraisopropoxytitanium and addition to 2-methylpropanal, the homoaldol adduct ( + )-4 with 73% ee, whereas (-)-4 (53 % ee) is obtained when chlorotris(diethylamino)titanium is used104. 

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