Methyllithium addition

The conversion of intermediate (72) to the natural product (73) was accomplished by exposure of a 1 1 complex of (72) and the hindered organoaluminum reagent (1 MAD) to methyllithium (57% yield). This is a fascinating result, not only because attempted methyllithium addition failed, but dso bKause the required configuration of the C-1 position was 3 with regard to the proton substituent and, therefore. 

The corresponding /ra j-substituted cyclopropanes cannot be obtained by the same method as alternative reaction pathways predominate. If, however, iodomethyllithium is used as a nucleophilic methylene transfer reagent (prepared in situ by methyllithium addition to diiodomethane), this drawback can be circumvented and rra/ix-substituted cyclopropanes are available with high diastereoselectivity. 

With 41 in hand, a two-step nitro reduction and protection, followed by partial reduction of the lactam and resulting cyclization furnished aminal 42. Further treatment with cyanogen azide generated Wcyanoamidine 43. Hydrolysis and amide protection followed by alkylation with allyl iodide yielded olefin 44 as a single diastereomer. Conversion of 44 to aldehyde 45 was the followed reaction of the mesylate with azide, a cross-aldol reaction with acetone, lactam reprotection with Boc, and trimethylphosphine-mediated reductive rearrangement to provide spiro-y-lactam 46. Methyllithium addition to lactam 46 and similar chemistry as reported by Qin et al. gave communesin F (17) (Scheme 6). 

Inner-phase guest orientation and mobility also control reactivity in through-shell borane and methyllithium additions to benzaldehyde 73, benzocyclobutenone 76, and benzo-cyclobutadione 77 inside hemicarcerand 6. ° BH3 THF reduced all three incarcerated guests to benzyl alcohol, ben-zocyclobutanol, and 7-hydroxybenzocyclobutanone (78), respectively (Figure 30). Guest reactivity differed from that in the liquid phase and increased in the order 77 76 > 73. 

Although ethereal solutions of methyl lithium may be prepared by the reaction of lithium wire with either methyl iodide or methyl bromide in ether solution, the molar equivalent of lithium iodide or lithium bromide formed in these reactions remains in solution and forms, in part, a complex with the methyllithium. Certain of the ethereal solutions of methyl 1ithium currently marketed by several suppliers including Alfa Products, Morton/Thiokol, Inc., Aldrich Chemical Company, and Lithium Corporation of America, Inc., have been prepared from methyl bromide and contain a full molar equivalent of lithium bromide. In several applications such as the use of methyllithium to prepare lithium dimethyl cuprate or the use of methyllithium in 1,2-dimethyoxyethane to prepare lithium enolates from enol acetates or triraethyl silyl enol ethers, the presence of this lithium salt interferes with the titration and use of methyllithium. There is also evidence which indicates that the stereochemistry observed during addition of methyllithium to carbonyl compounds may be influenced significantly by the presence of a lithium salt in the reaction solution. For these reasons it is often desirable to have ethereal solutions... 

The dry tosylhydrazone (20 g, 45.5 mmol) is dissolved in 750 ml of 1,2-dimethoxyethane (freshly distilled from lithium aluminum hydride) in a flame-dried 1 liter round bottom flask fitted with a 240 ml addition funnel, a drierite tube and a magnetic stirrer. A 2.05 M ether solution of methyllithium (130 ml, Alfa Inorganics, Inc.—Caution to avoid the mineral oil impurity the methyllithium solution is decanted from a cold solution which contains a precipitate) is placed in the dropping funnel and added over a 60 min period. The temperature of the reaction mixture increases to ca. 35° during the addition however, no cooling precautions are required. The highly colored reaction mixture is stirred for 7 hr and then poured into 1.5 liters of ice water. The flocculent precipitate is digested for 12 hr at room temperature to speed the filtration. After filtration the filter cake is washed with 500 ml water and dried under vacuum at 50° for several hr. The androsta-5,16-dien-3l5-ol is obtained in ca. 70% yield after recrystallization from methanol mp 138-139°. 

Addition of methylmagnesium bromide or methyllithium to 21-acetoxy-3,3 20,20-bisethylenedioxy-17a-hydroxypregn-5-ene-7,l 1-dione and subsequent acid treatment affords 7-methyl-A -cortisone. ... 

Kondrat eva pyridine synthesis. This methodology to pyridine rings continues to be applied in total synthesis. An approach to the antitumor compound ellipticine 34 ° makes use of a Diels-Alder reaction of acrylonitrile and oxazole 32 to form pyridiyl derivative 33. Addition of methyllithium and hydrolysis transforms 33 into 34. 

It was predicted, a priori, that isocomene could be formed simply by treating 4 with methyllithium, followed by exposure of the resultant tertiary carbinol to acid.2b However, many attempts to effect the addition of a variety of nucleophilic methyl derivatives to ketone 4 were unsuccessful. It was revealed by deuterium quenching experiments that ketone 4 undergoes ready enolization in the presence of nucleophilic methyl derivatives. Despite its hindered nature, however, the ketone carbonyl in 4 reacts with methylenetri-... 

The completion of the synthesis of the polyol glycoside subunit 7 requires construction of the fully substituted stereocenter at C-10 and a stereocontrolled dihydroxylation of the C3-C4 geminally-disub-stituted olefin (see Scheme 10). The action of methyllithium on Af-methoxy-Af-methylamide 50) furnishes a methyl ketone which is subsequently converted into intermediate 10 through oxidative removal of the /j-methoxybenzyl protecting group with DDQ. Intermediate 10 is produced in an overall yield of 83 % from 50) , and is a suitable substrate for an a-chelation-controlled carbonyl addition reaction.18 When intermediate 10 is exposed to three equivalents of... 

In a similar manner, 10-methyldibenz[Z>,/ oxepin (4) can be obtained from dibenz[6,/]oxepin-10-(1 l//)-one after addition of methyllithium and subsequent iodine-catalyzed dehydration.161... 

Unsubstituted oxepin reacts with methyllithium to give ew-6-methylcyclohexa-2,4-dien-l-ol216 and traces of the /runs-product,12 whereas the reaction with dimethylmagnesium gives a mixture of cis- and /rani-isomers in a ratio of 37 63.216 By using deuterated starting material it has been shown that a 1,6-addition takes place.216,217... 

The reaction of 3-benzoxepin with methyllithium results in the addition of two equivalents of the organometallic reagent and cleavage of the heterocycle. After hydrolysis l-[2-(Z)-prop-l-enyl)phenyl]propan-2-ol can be isolated, but no experimental data is available.216 Occasionally, a small amount of the tran.v-isomcr is obtained (less than 10% of the product).12... 

In contrast to its reaction with methyllithium, jV,Af-diethyl-5-phcnyl-3//-azepin-2-amine (1) with butylithium undergoes 4,5-addition to give 4-butyl-A, V-diethyl-5-phenyl-4,5-dihydro-3/7-azepin-2-amine (2)38. 

---