Exocyclic methylene compounds

The course of the ring opening in epoxides derived from various exocyclic methylene compounds by treatment with lithium aluminum deuteride has been studied in the norbornane series. ... 

Another route to a methyl-branched derivative makes use of reductive cleavage of spiro epoxides ( ). The realization of this process was tested in the monosaccharide series. Hittig olefination of was used to form the exocyclic methylene compound 48. This sugar contains an inherent allyl alcohol fragmenC the chiral C-4 alcohol function of which should be idealy suited to determine the chirality of the epoxide to be formed by the Sharpless method. With tert-butvl hydroperoxide, titanium tetraisopropoxide and (-)-tartrate (for a "like mode" process) no reaction occured. After a number of attempts, the Sharpless method was abandoned and extended back to the well-established m-chloroperoxybenzoic acid epoxida-tion. The (3 )-epoxide was obtained stereospecifically in excellent yield (83%rT and this could be readily reduced to give the D-ribo compound 50. The exclusive formation of 49 is unexpected and may be associated with a strong ster chemical induction by the chiral centers at C-1, C-4, and C-5. 

Thymidylate synthase (TS) is the enzyme that converts 2-deoxyuridine monophosphate into thymidine monophosphate. This is a key step in the biosynthesis of DNA. This enzymatic reaction of methylation involves the formation of a ternary complex between the substrate, the enzyme, and tetrahydrofolic acid (CH2FAH4). The catalytic cycle involves the dissociation of this complex and the elimination of FAH4. It is initiated by pulling out the proton H-5, thus generating an exocyclic methylene compound. As the release of a F" " ion is energetically forbidden, the fluorine atom that replaces the proton H-5 cannot be pulled out by the base. This leads to inhibition of the enzyme (Figure 7.2). 

With the exception of compound 75 none of these compounds were active. Since the exocyclic methylene analog 75 had activity we chose to prepare a simplified analog [Fig. (23)]. Thus, the catechol 66 was reacted with 79, K2CO3 and Nal in DMF for 16 h to give the exocyclic methylene compound 80 which lacked the C26 dimethyls. Compound 80 was inactive, which further emphasizes the importance of C26 dimethyls. 

NMR was used to distinguish 2,2,4,6-tetramethyl-2//-pyran from the isomeric exocyclic methylene compound (32) into which it is converted on treatment with acid (64BSF1492). 

Cycloaddition reactions of the chiral exocyclic methylene compounds A and B derived from menthone and of related chiral 1-oxa-l,3-dienes (C) with alkenes as dienophiles, e.g. ketene acetals, proceed smoothly and are highly stereoselective. ... 

The B-alkyl-9-BBN undergoes an interesting reverse reaction to afford the parent alkene when treated with benzaldehyde. Consequently, the reaction is uniquely employed for the synthesis of exocyclic olefins (Chart 24.3). The hy-droboration of cyclic olefins with an internal double bond, followed by homologation with carbon monoxide in the presence of lithium trimethoxyaluminum hydride afford B-(cycloalkylmethyl)-9-BBN. This intermediate on treatment with benzaldehyde leads to an exocyclic methylene compound (Chart 24.3) [16]. Since the synthesis proceeds from the cycloalkene, thus it provides a valuable alternative to the customary methylenation of carbonyl compounds by Wittig and related procedures. The method also provides a clean synthesis of deuterium-labeled compounds (Eq. 24.10) [16], without positional scrambling or loss of label. Consequently, methylmethylene-d -cyclopentane in 52% isolated yield is obtained. 

The spiro compound (239) was synthesized via the unstable exocyclic methylene compound (238) in a Simmons-Smith reaction, in which the methylene group was converted to a cyclopropane ring. The aldehyde (240) was obtained in the form of a pure isomer from (239) by reduction, oxidation, and purification by HPLC. In the final step, (240) was reacted with the C5 phosphonate (166) to give a mixture of the esters (241) and (242). From this mixture, the all-trans isomer (241) and the 13-cis compound (242) were isolated in chromatographically pure form. 

In the third sequence, the diastereomer with a /i-epoxide at the C2-C3 site was targeted (compound 1, Scheme 6). As we have seen, intermediate 11 is not a viable starting substrate to achieve this objective because it rests comfortably in a conformation that enforces a peripheral attack by an oxidant to give the undesired C2-C3 epoxide (Scheme 4). If, on the other hand, the exocyclic methylene at C-5 was to be introduced before the oxidation reaction, then given the known preference for an s-trans diene conformation, conformer 18a (Scheme 6) would be more populated at equilibrium. The A2 3 olefin diastereoface that is interior and hindered in the context of 18b is exterior and accessible in 18a. Subjection of intermediate 11 to the established three-step olefination sequence gives intermediate 18 in 54% overall yield. On the basis of the rationale put forth above, 18 should exist mainly in conformation 18a. Selective epoxidation of the C2-C3 enone double bond with potassium tm-butylperoxide furnishes a 4 1 mixture of diastereomeric epoxides favoring the desired isomer 19 19 arises from a peripheral attack on the enone double bond by er/-butylper-oxide, and it is easily purified by crystallization. A second peripheral attack on the ketone function of 19 by dimethylsulfonium methylide gives intermediate 20 exclusively, in a yield of 69%. 

Quinone methides (QMs), especially the simple ones (those not having substituents at the exocyclic methylene group), are very unstable compounds. Their isolation is very difficult and normally requires very dilute solutions and low temperatures.2 Due to the aromatic z witterionic form (Scheme 3.1), quinone methides react very rapidly with both electrophiles and nucleophiles, with the medium, or in self-condensation reactions. 

The final stages of the synthesis of (—)-A-58365B, a Streptomyces metabolite that inhibits the angiotensin-converting enzyme, involve several reactions at substituents attached to ring carbon atoms of a quinolizidine system. Thus, ozonolysis of the exocyclic methylene side chain of compound 107, followed by base-induced elimination and carboxyl deprotection, gave 108 (Scheme 12) <1999JOC1447>. 

Axisonitrile-1 (1) and axisothiocyanate-1 (2) were the first pair of NC/NCS compounds isolated from Axinella cannabina, see Introduction [1]. That both compounds possessed a new skeleton was evident, when 1 was reduced (Li/EtNH2) to axane (6). Other transformations involving the exocyclic methylene which survived selective reduction (Na/NH3) of 1, coupled with evaluation of the lHNMR data, supported its gross structure. Confirmation of 2 was secured when 1 was heated with sulfur and the resultant purified product found to be identical to the natural product. 

Carbocyclic compounds containing an unsubstituted exocyclic methylene group give 1,2-diazetidines with PTAD. Methylene adamantane gives the adduct 47,8 5 and the methylene cyclopropane (48, R = H) gave the 1,2-diazetidine 49.86 The phenyl-substituted compound (48, R = Ph) behaved similarly to styrene and gave a 2 1 adduct with PTAD (see Section IV,D,1). 

The discovery of the ethylidenecarbapenems, the asparenomycins, as naturally occurring /J-lactamase inactivators in the early 1980s was another striking point in /J-lactamase inhibitor research. The substituted exomethylene function in asparenomycins is a distinctive feature of this class of compounds, which many scientists recognized could be a key factor for /J-lactamase inhibition. The exo cyclic methylene is expected to increase the acylation ability, and form an a,/J-unsaturated ester of the active site serine residue as an acyl-enzyme complex. This ester will be similar in structure to the acyl-enzymes formed from clavulanate and sulfone fragmentation, and will be quite resistant to hydrolytic deacylation. Thus, the exocyclic methylene promotes acylation by the enzyme and subsequently represses deacylation. Based on... 

The H NMR spectram (CDClj, 500 MHz) of 12 showed two singlets (8 0.83 and 8 0.95), each integrating for three protons due to the C-18 and C-19 methyl protons. Three 3H doublets at 8 0.78 (J= 6.5 Hz), 8 0.79 (J= 6.5 Hz) and 8 0.85 (J = 7.0 Hz) were due to the secondary C-26, C-27 and C-21 methyl protons, respechvely. The C-3 methine proton resonated as a one-proton double doublet at 8 3.63 (JJ= 10.5 Hz and J2= 3.5 Hz) and its downfield chemical shift value was indicative of the presence of a geminal hydroxyl funchonality. A one-proton mulhplet at 8 5.21 was ascribed to the C-6 olefinic proton. The C-28 exocyclic methylene protons appeared as two broad singlets at 8 5.40 and 5.58. The C-NMR spectram (CDCl, 125 MHz) showed the resonance of all 28 carbon atoms. The combination of H and C-NMR data suggested that compound 12 has a sterol like structure as most of the H and C-NMR chemical shift values of 12 were similar to those of sterols reported in the literature [19, 20]. The H and C-NMR chemical shift values were assigned with the aid of COSY-45 , HSQC and HMBC spectral data. Compound 12 was found to have modest inhibitory activity against C. xerosis and S. aureus with minimal inhibitory concentration values of 82.35 and 146 pg/ml, respectively. 

The alternative structural situation of an exocyclic methylene group in conjugation with a ring oxygen is found in methylene-4-pyrans (vinylogous pyrones), in which a 4-pyrone-like resonance [230] occurs. These compounds are little known. Their synthesis... 

Studies directed toward the synthesis of bicyclomycin have resulted in the discovery of efficient routes to the construction of the 2-oxa-8,10-diazabicyclo[4.2.2]decane system (160). Thus, the monolactim ether (155) with a hydroxypropyl side chain at position 3, on oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), gave the product (156) in good yield, presumably via an iminium species (Scheme 51). No trace of the spiro compound (157) could be detected in this reaction. The formation of (156) is probably kinetically controlled. Prior protection of the alcohol as a silyl ether, followed by DDQ oxidation, gave the pyrazinone (158) subsequent deprotection and acid treatment gave the thermodynamically preferred spiro compound (159). The method has been extended to the synthesis of (160), having an exocyclic methylene this compound is a key intermediate in the total synthesis of bicyclomycin [88JCS(P1)2585]. 

In the infrared, the exocyclic methylene derivatives show stretches in the ranges 1750-1790 and 1510-1550 cm7, respectively, that compare well with the observed ranges of 1810-1880 and 1510-1550 cm 1 for substituted methylenecyclopropenes11,305 and are due to coupling between the endo- and exocyclic w-bonds. The move to lower wavenumber of the higher-energy stretch is consistent with the polar nature of the compounds. 

These alkaloids are a relatively small group within the isoquinoline family. Ochotensimine (101) was the first to be studied and it and ochotensine are the only compounds of the group that have an exocyclic methylene on the five-membered ring (2, 3, 62). The most common functional groups are carbonyl, hydroxyl, or acetoxy at one or both of C-8 and C-13. The spectra of a series of these alkaloids were reported in 1977 (63) and these data were used recently in the structural elucidation of a new alkaloid (64). The structures and spectral data on the alkaloids discussed in this section may be found in Fig. 19 and Table XVIII, respectively. They are ochotensimine (101), sibiricine (102), corydaine (103), ochrobirine (104), fumaritine (105), and fumaritine A-oxide (106). 

The reduction was carried out applying a household microwave oven. In contrast to the Zn-AcOH reduction of Parthenin, which was performed under conventional heating conditions, the microwave-assisted protocol was found to be useful in preventing the deoxygenation of the compound and the reduction of the exocyclic methylene group. 

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