Enediyne alcohols

Bergman cyclization of the enediyne alcohol 985 gave the tetrahydrobenzoquinazoline 986, both thermally and photochemically in isopropanol, while the analogous ketone only showed efficient thermal cyclization <20000L3761>. 

The first issue confronted by Myers was preparation of homochiral epoxide 7, the key intermediate needed for his intended nucleophilic addition reaction to enone 6. Its synthesis began with the addition of lithium trimethylsilylacetylide to (R)-glyceraldehyde acetonide (Scheme 8.6).8 This afforded a mixture of propargylic alcohols that underwent oxidation to alkynone 10 with pyridinium dichromate (PDC). A Wittig reaction next ensued to complete installation of the enediyne unit within 11. A 3 1 level of selectivity was observed in favour of the desired olefin isomer. After selective desilylation of the more labile trimethylsilyl group from the product mixture, deacetalation with IN HC1 in tetrahydrofuran (THF) enabled both alkene components to be separated, and compound 12 isolated pure. 

Allenyl phosphine oxides (75) have been prepared by the reaction of the enediyne alcohols (74) with chlorodiphenylphosphine. When heated at 37°C in the presence of 1,4-cyclohexadiene, (75) gave mixtures of aromatic compounds (76), (77) and (78) (Scheme 12). Evidence for the biradical (79) acting as an intermediate was obtained by heating (75) i n perdeuterotetrahydrofuran. O The enediyne alcohol (74, R = CH2CH20Ac) shows DNA-cleaving activity which is presumably related to diradical formation. ... 

Cyclic enediynes have been obtained also by elimination of a suitable propargylic alcohol on a preformed cyclic diyne.5 An example is shown in Scheme 19.7, where the cyclization was accomplished through a Nozaki-Hiyama intramolecular allyl bromide addition to an aldehyde.5 This method proved successful for the synthesis of a particular enediyne that, because of conformational biases, could not be obtained by the strategies described above. 

Alcohols of general formula 27 may also be obtained by base-promoted [2,3] Wittig sigmatropic rearrangement. This method has been applied for the synthesis of 9-membered cyclic enediynes. ... 

The best results have been obtained so far with compounds 39 and 40 (Scheme 19.9). In the first one, the enediyne is bonded to the minor groove binder netropsin through a semirigid linker. It displays a 2000-fold increase in activity compared to the parent alcohol. With an EC50 of about 200 nM, it is probably the most potent artificial enediyne prepared so far. However, it is still 10 times less active than calicheamicin and, most of all, no double strand cleavage was detected. Compound 40 contains a DNA intercalator and has an EC50 of 80 pM and a D/S ratio of 1 18. ... 

Ru(Tp)(PPh3)(MeCN)2]PFg has been employed as catalyst to produce l-iodo-2-naphthol in DMF and 2-iodobenzo[d]oxepin in benzene from l-(2/-iodoethynylphenyl)-2-propyloxirane. The solvent-dependent chemoselectivity has been ascribed to a solution equilibrium between ruthenium-Tt-iodoalkyne and ruthenium-2-iodovinylidene intermediates.66 The same ruthenium phosphine complex has been efficiently employed as catalyst in the nucleophilic addition of water, alcohols, aniline, acetylacetone, pyrroles, and dimethyl malonate to unfunctionalized enediynes that yielded functionalized benzene products in good yields (Fig. 8.6).67 [Ru(Tp)-(PPh3)(MeCN)2]PFg has been also found very active in catalytic benzannulation of l-phenyl-2-ethynylbenzenes in dichloroethane to afford phenanthrene.68... 

Fig. 8.6. The nucleophilic addition of water, alcohols, pirroles, and Hacac to unfunctionalized enediynes yields functionalized benzene derivatives.

The procedure outlined above describes the selective, retentive, p-coupling of (Z)-2,3-dibromopropenoic acid ethyl ester with (trimethylsilyl)acetylene employing the palladium-modified version of the Castro-Stephens reaction.4 5 The dibromide starting material is readily available by bromination of ethyl propiolate (Procedure A), as described by Trippett and Hall.2 The coupling product has been shown to be a versatile precursor for the synthesis of variously substituted enynes and enediynes. For example, a second acetylene may be introduced into the a-position under modified coupling conditions. Alternatively, reduction of the ester with diisobutylaluminum hydride and protection of the resultant alcohol with tert-butyldiphenylsilyl chloride affords a vinyl bromide that can be metalated and trapped with various electrophiles. These procedures have been used on the gram and multigram scale.5... 

A synthesis of the tetrahydroquinoline enediyne structure (6) of the antibiotic dyncmicin2 involves condensation of a Co(CO)6-protected propargylic alcohol with an enol.-1 Thus treatment of 4 with triflic anhydride and 2,6-di-r-butyl-4-methylpyridinc in CH2CI2/CH3NO2 results in 5 in 52% yield. (Use of nitromethane is crucial for satisfactory results.) This product on dccomplexation with iodine provides 6, which undergoes aromatization when heated to form 7. 

In a model reaction for the preparation of the esperamicin/calicheamicin aglycones (Scheme 2-20) the enediyne alcohol 175 is converted into the terminal iodo derivative 176 by... 

With this critical reaction beautifully orchestrated, all efforts could now be directed towards closing the final juncture of the 10-membered enediyne ring, a requirement whose implementation was projected to involve the addition of an acetylide ion to a suitable group at C-7. However, since this operation would ultimately lead to the excision of the alcohol function at C-7, it was decided to use this motif productively for one additional operation before attempting its displacement, namely directing the formation of the central C3-C8 endocyclic epoxide. Thus, 49 was treated with mCPBA in buffered CH2CI2 at 0 C, giving rise to 50 in 88% yield with complete facial selectivity for the drawn product. Next, treatment of 50 with TB AF in THF at 0 °C, followed by silyl reprotection of the phenolic position under standard conditions (TBSCl,... 

The transformation of enantiomerically enriched 1,1,4-trisubstituted but-2-yne-l,4-diols (262) into 2,2,5-trisubstituted 3-acyloxy-2,5-dihydrofurans (267) with complete stereospecificity has been achieved by an Ag(I)-mediated rearrangement of the monoesters (263) to allenic intermediates (265), followed by Ag(I)-assisted cycUzation. A possible mechanism for the rearrangement and cyclization is shown in Scheme 66, in which the carbon-oxygen bond (b) in (266) is formed from the back side of the carbon-oxygen bond (a) in (264). A novel synthetic method has been developed for the rearrangement of 3-aryl-l,2-dialkynylallyl alcohols into m-enediynes under mild acidic conditions. The allylic rearrangement has been shown to involve an acid-catalysed isomerization step to convert the allyl alcohol into an allylic cation... 

The Mitsunobu reaction (PPhs/DEAD) in the presence of HSTIPS has been used to convert the enediyne primary alcohol in eq 6 to the protected sulfide, which is readily converted upon treatment with CsF/DMF and PhthNSSMe to the corresponding disulfide. ... 

An unusual overcrowded polycyclic structure 3.577 was obtained by the reaction of the propargyl type enediyne alcohol 3.576, a truxenone derivative, with thionyl chloride in pyridine. A cascade of reactions... 

Several helical polycyclic aromatic hydrocarbons bearing aryl substituents at the most sterically hindered position were synthesized in an efficient three-step cascade reaction. The initial benzannulated enediynes were synthesized by the reaction of appropriate lithium acetylenides with an aryl-rert-butyl ketone. This was followed by reduction of the resultant acetylenic propargyl type alcohol with triethylsilicon hydride. This method turned out to be particularly successful for the synthesis of helical molecules. The reaction of ketones 3.588 and 3.590 with the lithium derivative of l-ethynyl-2-(2-penylethynyl)benzene 3.545 or related binaphthyl derivative followed by reduction and three-step sequence of cascade reactions led to polycyclic aromatic compounds 3.589 and 3.591, respectively, in a good yield (Scheme 3.48) [294, 295]. 

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