2,5-Dimethoxybenzyl alcohol: a convenient self-indicating standard for the determination of organolithium reagents

The total synthesis of the naturally occurring fluorenone, dengibsinin (7a), and the azafluoranthene alkaloid, imeluteine (30e), is described. Using combined ortho metalation -cross coupling sequences that terminate in Friedel-Crafts (186 + 6 4 and remote metalation (21a,b + 6 c , 4 reactions, the synthesis of fluorenone dimethyl ethers 6c and 6d is reported. 6c and 6d were shown not to be identical to dengibsinin dimethyl ether and dengibsin dimethyl ether, respectively, derived from the natural products. This work, together with synthetic and structural evidence from Sargent and Talapatra, led to the reassignment of structures for dengibsinin (7a) and dengibsin (76). Using the metalation -cross coupling approach, the synthesis of the reassigned dengibsinin (70) is presented. Two alternate unsuccessful approaches to imeluteine are briefly described (31 + 32 and 33 + 34). During the course of work aimed to establish synthetic links between the Directed ortho Metalation (DoM) strategy (1) and transition metal catalyzed cross-coupling reactions (2), the concept of the complex induced proximity effect (CIPE) was unified and brought into prominence by Beak and Meyers (3) and by Klumpp (4). This concept defines pathways in which functional group -reagent preequilibrium complexation is a significant event prior to subsequent irreversible, and necessarily intramolecular, reaction at a proximate site. While CIPE is undoubtedly of broader mechanistic value (3), it has been most notably invoked in organolithium transformations to rationalize formation of (a) surprising kinetic in lieu of expected thermodynamic products and (b) substantial accelerations of normally unfavorable reactions. As a consequence, it has created new opportunities in the design of regio-and stereo-specific reactions. In contemplating the X-ray structure of a 2,6-diphenyl b e n~a m i d e ,~ we reasoned that such complexation and entropic factors may induce remote metalation in 1 (Scheme 1) as a function of H1/H2 hydrogen relative acidities to give species 2, which could cyclize to fluorenone 3 in an intramolecular version of the classical amide-RLi condensation reaction. Such a reaction would constitute an anionic Friedel-Crafts equivalent with the following advantages over the latter process: (a) mild conditions, which would tolerate greater functional group diversity; (b) regioselectivity dictated by the availability of directed metalation groups (DMGs) in the aromatic ring in which the incipient carbanion is generated, i.e., 2, X = OMe; (c) complementarity, i.e., 2 + 3 vs. 1 + 4, X = OMe; and (6) chemoselectivity, i.e., avoidance of dibenzopyranone product 5 in acid-sensitive oxygenated systems 1, Y = OPG (see below).Herein we report4 the application of this remote aromatic metalation concept for the construction of the naturally occurring fluorenone dengibsinin (7a) and the azafluoranthene alkaloid, imeluteine (30e). In a sequel,3 we shall present general methodological results on the ~u z u k i cross-coupling reaction for precursor teraryls 1 an...

Section: General Proceduresmentioning

confidence: 99%

ortho and remote metalation – cross coupling strategies. Total synthesis of the naturally occurring fluorenone dengibsinin and the azafluoranthene alkaloid imeluteine

Fu¹,

Zhao²,

Sharp³

et al. 1994

“…Vinylmagnesium bromide was purchased from the Aldrich Chemical Co. 2-Propenyllithium and 2-methyl-I-propenyllithium were titrated with diphenylacetic acid (26), (E)-1-propenylmagnesium bromide was titrated using 1,10 phenanthroline and sec-butyl alcohol (27), and n-butyllithium was titrated with 2,5-dimethoxybenzyl alcohol (28). Aldehyde 2b (29), allylic alcohol 7 (6), and di-(2,4,6-trimethylphenyl) diselenide (30) were synthesized according to literature methods.…”

Section: Methodsmentioning

confidence: 99%

Stereoselectivity of directed epoxidations of 22-hydroxy-Δ²³-sterol side chains

Back¹,

Baron²

1996

A series of 22-hydroxy-A''-sterols comprising (3~,5a,6~,22S)-6-methoxy-3,5-~y~l0-25,26,27-trinorcholest-23-en- 22-01 (6), (3~,5a,6~,22S,23E)-6-methoxy-3,5-cyclo-26,27-dinorcholest-23-en-22-ol (7), 3P,5a,6P,22R)-6-methoxy-23-methyl-3,5-cyclo-25,26,27-trinorcholest-23-en-22-ol(10), 3~,5a,6~,22S,23~-6-methoxy-3,5-cyclo-26,27-dinorcholest-23-en-22-01 ( l l ) , and 3~,5a,6~,22R)-6-methoxy-3,5-cyclo-26,27-dinorergost-23-en-22-ol (12) were subjected to epoxidation with /)I-chloroperbenzoic acid and [err-butyl hydroperoxide in the presence of either vanadyl acetoacetonate or molybdenum hexacarbonyl, and the rhreo:eryrhro ratios of the products were determined. The results are of relevance for the synthesis of sterols with oxygenated side chains, such as brassinolide (I). The oxidations of 6 and 7 were er.y~hro selective with all three oxidants, especially with the vanadium-catalyzed system. Peracid oxidation of the 22-[err-butyldimethylsilyl ether (8) and 22-pivaloate (9) of alcohol 7 showed similar elyrhro selectivity to that of the parent compound 7. Allylic alcohol 10 gave exclusively the eryrhro epoxide with all three oxidants, while 11 and 12 were threo-selective under all three conditions. Molecular modeling indicated that eryrhro selectivity in the vanadium-catalyzed epoxidation of 10 was consistent with a destabilizing interaction (~( 1 . 2 1 strain) between the getn-methyl and C(2 I) methyl groups in the conformation required for formation of the rhreo-isomer. The ttrreo-selective peracid oxidations of 11 and 12 were attributed to A''.~) strain between the cis-methyl groups and C(20) in the conformation required for formation of the etyrhm-epoxide. The differences in the calculated energies of conformations leading to the rhreo-and eryrhro epoxide diastereomers of substrates containing no gem or cis substituents proved too small to permit reliable prediction of diastereoselectivity.Key words: 22-hydroxy-A'3-stero~s, brassinosteroids, allylic alcohols, epoxidation, diastereoselectivity I R6sumC : On a soumis une sCrie de 22-hydroxy-Ax-st~rols, comportant les (3P,5a,6P,22S)-6-mCthoxy-3,5-cyclo-25,26,27-trinorcholkst-23-Cn-22-01(6), (3~,5a,6~,22S,23E)-6-mCthoxy-3,5-cyclo-26,27-dinorcholkst-23-en-22-ol(7), 3P,5a,6P,22R)-6-mCthoxy-23-mCthyl-3,5-cyclo-25,26,27-trinorcholCst-23-Cn-22-ol (lo), 3P,5a,6P,22S,23~-6-mCthoxy-3,5-cyclo-26,27-dinorcholkst-23-en-22-01 ( l l ) , et 3~,5a,6~,22R)-6-mCthoxy-3,5-cyclo-26,27-dinorergost-23-n-22-o (12), i une Cpoxydation par I'acide tn-chloroperbenzo'ique et l'hydroperoxyde de re,?-butyle, en prksence soit d'actoacCtonate de vanadyle soit d'hexacarbonyle de molybdkne; on a dCterminC les rapport rhrio/e'ryrhro des produits obtenus. Les rtsultats prCsentent de I'importance pour la synthkse de stCrols portant des chaines IatCrales oxygCnCes, comme le brassinolide (1). Les oxydations des composes 6 et 7 sont tryrhro-stlectives avec chacun des trois oxydants, particulikrement avec le systkme catalysC par le vanadium. Les oxydations du 22-terr-butyldimCthylsilyloxyde (8) et du 2...

“…Lithium chloride was dried at 130°C and used directly. n-BuLi was periodically titrated using 2,5-dimethoxybenzyl alcohol as the indicator (12).…”

Section: General Methodsmentioning

confidence: 99%

Enantioselective deprotonation of protected 4-hydroxycyclohexanones

Majewski¹,

MACKINNON²

1994