5-C- methylene derivatives

As part of an investigation into developing routes to natural sesquiterpinoid ring systems, the application of the Pausen-Khand reaction has led to some unexpected results. Thus the fused [3.3.0]bicyclooctenone-pyranose system 45 was produced as expected when the 3-C-methylene derivative 46 was treated with Co(CO)g in an atmosphere of carbon monoxide. However, the fused [4.1.0]bicy-cloheptene-pyranose system 47 was produced from the 4-C-methylene derivative 48 under similar conditions. ... 

The regioselectivity of the addition of diazomethane to a series of 3-C-methylene derivatives e.g. Scheme 99) has been examined, particularly with regard to the stereochemistry and nature of the substituents at C-3. ... 

Brimacombe s group have used the addition of mercuric azide to the 3-C-methylene derivative (262) to prepared branched-chain amino-sugars [e.g. (263)] as outlined in Scheme 100. - The conversion of the branched-chain azide... 

A further study of the use of the Arndt-Eistert reaction in carbohydrate chemistry examined the reactions of the diazoketone (247) (prepared from a-D-glucoisosaccharinic acid), which gave mainly the orthoester (248) and both the ( )- and (Z)-isomers (249) of a 2,3-unsaturated methyl hexonate derivative on treatment with silver oxide in methanol. The 3-C-methylene derivative (248) is a useful precursor of 4-deoxy-3-C-methyl-D-hexoses. 

Y. Ali and W. A. Szarek, Synthetic approaches to gem-di-C-alkyl derivatives of carbohydrates Nucleophilic addition reactions of 3-C-methylene compounds derived from l,2 5,6-di-0-isopropylidene-ot-D-rifto-hexofuranos-3-ulose using phase transfer catalysis, Carbohydr. Res. 67 Cll (1978). 

Dimethyl-2,3-dihydro-1,8-naphthyiidin-4(l//)-one (38) gave its 3-hydroxy-methylene derivative (39) (Et02CH, NaOEt, PhH, 20°C 81%) that underwent oxidation in refluxing benzene to afford l,7-dimethyl-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carbaldehyde (40) as the main product ( 45%).1394... 

An analogous methyl 2,3-dideoxy-3-C-methylene-a-L-en/thro-hexopyranoside (20) was obtained10 from methyl 4,6-O-benzylidene-2-deoxy-a-L-eri/t/iro-hexopyranosid-3-ulose (19) it was used in the synthesis of olivomycose (see p. 242). There was also reported32,34 the preparation of 3-deoxy-l,2 5,6-di-0-isopropylidene-3-C-methyl-ene-a-D-rifco-hexofuranose (22) from 1,2 5,6-di-0-isopropylidene-a-D-nfeo-hexofuranos-3-ulose (21) in about 60% yield, followed by transformations into branched-chain sugar derivatives, including... 

Cook reported the syntheses of phosphonamidite and H-phosphonates derivatives of 3 -C-methylene modified thymidines (77a-e), 3 -C-methylene 5-methyl-iV-pyrrolidine-modified cytosine (78) and 3 -C-methylene 5-methyl modified uridine (79) having methoxy, fluoro, hydrogen and methoxyethoxy substituents at the 2 -positions. The H-phosphonates were synthesised from the corresponding key intermediate 3 -C-iodomethyl nucleosides through an... 

The synthesis of polytartaramides was first reported by Minoura and coworkers.79 During the 1970s, Ogata et a .80-81 described the polycondensation of tartaric acid itself or its 2,3-69-methylene derivative with diamines, by a variety of procedures. These authors also studied the copolymerizations of diethyl-L-tartrate with other diesters64 and reported that the rate of polymerization of dimethyl-L-tartrate with 1,6-diaminohexane in dimethyl sulfoxide at 60°C increased when the reactions were conducted in the presence of such polymer matrices as poly (vinyl pyrrolidone), pullulan, and poly (vinyl alcohol). The rate increased with increasing molecular weight of the matrix.82... 

The branched-3-C-methyl derivative 32 was formed stereoselectivity and in high yield when dimethylcopper lithium in the presence of TmsCl added 1,4-fashion to the corresponding 2,3-unsaturated lactone. Several similar examples were also described including addition of active methylene compounds e.g. diethyl malonate under basic conditions). ... 

The 2-C-methylene derivatives (17) are available by condensation of 1,1-di-methoxyprop-2-en-2-yl-lithium with 2,3-O-isopropylidene-D-glyceraldehyde, with the erythro-isomcx predominating over the t/zreo-isomer (7 3). Methanolysis of (17) afforded methyl 2-deoxy-2-C-methylene-j3-D-e/ yf ro-pentopyranoside and methyl 2-deoxy-2-C-methylene-0 -L-r)i/ eo-pentopyranoside from the erythro-... 

In connection with the modification of Everninomicin D, the electrochemical reduction of the 3-C-methyl-3-nitropyranoside (22) has been studied. In an acetonitrile solution of tetraethylammonium tetrafluoroborate as the supporting electrolyte, it afforded a mixture of the 3-C-methylene (23) and 3-C-methyl (24) derivatives and a dimer (25), resulting presumably from the C-3 radical (26), in 36%, 14%, and 2% yield, respectively (Scheme 6). The reaction was then carried out with the intact antibiotic to give three new analogues. ... 

The glycosidulose (254) reacted with methylene triphenylphosphorane in toluene to give the 2-C-methylene derivative (255), which was converted into methyl 4,6-0-benzylidene-2-deoxy-2-C,3 0-dimethyl-a-D-gIucopyranoside on catalytic hydrogenation over Raney nickel. However, the enone (256) (58%) preponderated when the Wittig reaction was carried out in more polar solvents such as DMSO. 

Addition of mercuric azide to l,2 5,6-di-0-isopropylidene-3-C-methylene-a-D-r/6o-hexofuranose yielded, after reductive demercuration, the branched-chain azide (291), which could be transformed into the corresponding acetamido derivative (292). The conversion of (291) into the 3,6-acetylepimino derivative (293) established that it has the n-gluco configuration (see Vol. 9, p. 106). 

Protected and partially 0-protected glycals (but not 3,4,6-tri-0-/erf-butyldi-methylsilyl-D-glucal) can be readily cyclopropanated with diiodomethane-diethyl-zinc to afford intermediate 1,2-C-methylene derivatives. Treatment of these latter compounds with Lewis acids was expected to produce intermediate ring-expanded oxonium ions 24 which should be readily trapped witii a nucleophile to give oxepane derivatives. This proved to be the case when cyclopropane derivative 25 was treated with trimethylsilyl triflate in the presence of trimethyl-silyl cyanide as internal nucleophile to give oxepane 26. Cyclopropane derivative 27, under similar conditions but with allyltrimethylsilane as nucleophile, reacted intramolecularly to oxepane... 

Lombardo methylenation (zinc-dibromomethane-titanium tetrachloride) of methyl 2-deoxy-5-0-(4-phenylbenzoyl)-P-D-g/ycero-pent-3-uloside, followed by dihydroxylation, gave the 3-C-hydroxymethyl derivative 7 (R = 4-phenylbenzoyl) exclusively. A ran of other 2-deoxypentuloses was also subjected to a similar course of reactions, but erally resulted in the formation of epimers during the dihydroxylation step. The hydroxymethyl group was further transformed first with tosyl chloride to the tosylate which was displaced with adenine or thymine to yield nucleoside analogues. ... 

Deoxy-l, 2 5,6-di- O-isopropylidene-3- C-methylene-a-D-ri2>o-hexofuranose has been converted in several steps to the branched-chain compound 18 as a precursor to 2, 3 -dideoxy-3, 4 -dihydroxymethyl pyrimidine nucleosides. The hydroxymethyl group at C-4 was introduced by way of a crossed aldol condensation of a 5-formyl derivative with formaldehyde followed by a Cannizaro reduction of the intermediate hydroxy aldehyde in a similar manner to that previously described in Vol. 13, p. 126, ref. 16. ... 

An asymmetric synthesis of ethyl 2,3-dideoxy-4-C-methyl-3-C-methylene-D-g/ycero-pentofuranosides has been described. Thus, regioselective cyclization of the chiral acetal 62 (derived from 2,3-dimethyl-2-butenal) under acidic conditions. 

The 3-C-methylene glycosyl phosphate 64 in which the methylene group is acting as a masked keto group has been prepared in several steps from a 3-C-methylene-D-glucose intermediate and used to prepare a nucleoside diphosphate derivative central to the biosynthesis of di- and tri-deoxysugars. ... 

The use of 3-chloro-3-phenylprop-2-enylidenedimethylyiminium perchlorate in the synthesis of C-3-exocyclic methylene derivatives has been reported (Sdieme 14). ... 

An important use of H CHO has been found in amino[ " C]methylations of nucleophiles in the presence of primary and secondary amines (Mannich reaction). Nucleophilic substrates include C—H acidic aliphatic compounds (e.g. aldehydes, ketones, esters, nitroalkanes and nitriles), and reactive aromatic and heteroaromatic substrates such as indoles, furans and phenols. The amino[ C]methylations of some C—H acidic methyl, methylene and methine substrates are exemplified in Figure 5.44. The immediate products, alkyl- or dialkylamino[ C]methylene derivatives ( Mannich bases ), can undergo a number of useful synthetic transformations. Condensation of H CHO with acetophenone and dimethylamine provided the carbon- 14-labeled /3-aminoketone 147 in 51 % yield. /3-Aminocarbonyl compounds such as 147. whQe stable at room temperature, can eliminate... 

Diketene is used to C-acetoacetylate aromatic compounds in the presence of aluminum trichloride [7446-70-0]. Benzene [71-43-2] and diketene react to produce acetoacet5lben2ene [93-91-4]. Pyrrole [109-97-7] and diketene react to produce 2-acetoacet5lpyrrole [22441-25-4]. The C-acetoacetyl derivatives of active methylene compounds such as cyanoacetates, malonodinitrile [109-77-3] and Meldmm s acid [2033-24-1], and olefins can be prepared using diketene. 

In like manner lodal (VI), on condensation with 6-nitro-3 4-methylene-dioxyphthalide (IV) yields nitro-a -adlumine (I R = NOj . O. CHa. O. at C and C replaced by 20Me), which crystallises from chloroform-methyl alcohol in orange, rectangular plates, m.p. 180-1° dec.), and on reduction yields the corresponding amino-derivative, bundles of minute needles, m.p. 218-9°. 

According to a detailed mechanistic study, the first step is the abstraction of the relatively acidic hydrazone proton (93- 97). This is followed by hydride attack on the trigonal carbon of the C=N bond, mainly from the a-side at C-3, together with the concomitant loss of the tosylate anion (97 -> 98). Expulsion of nitrogen from the resulting intermediate (98) yields a fairly insoluble anion-metal complex (99) which upon decomposition with water provides the methylene derivative (100). 

Secrist, S. Y. Babu, C. E. Bugg, W. C. Guida, and S. E. Ealick, Structure-based design of inhibitors of purine nucleoside phosphorylase, 3,9-arylmethyl derivatives of a 9-deazaguanine substituted on the methylene group, J. Med. Chem. 36 3771 (1993). 

Danieli et al. 116), both of which utilize an alkylation process of 1-methyl-3,4-dihydro-(3-carboline (150) in the key ring-forming step. In the first one, treatment of 150 with a-methylene- y-butyrolactone gave enamide 172, which, when reduced with lithium aluminum hydride, afforded indolo[2,3-a]quinolizine derivative 173. The desired ethylidene substituent at C-20 has been developed from the hydroxyethyl side chain in a four-step sequence as shown below. 

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