Exocyclic reactions compounds

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). 

The intermediacy of an anhydro base (57) was referred to in Scheme 46. Analogous anhydro bases (pyridone methides) can be formed by deprotonation of quaternary salts of 2- and 4-benzylpyridines and the like. The pyridone methides are usually highly reactive and not readily isolable some stable examples are shown in Scheme 49. Pyridine methides are intermediates in the base-catalyzed alkylation and acylation reactions of pyridinium salts at the exocyclic carbon. Compounds of type (60) have been estimated to have 25-30% dipolar character. Protonation of (60) occurs at the 2 - and 3 -positions in the ratio 4 1 respectively (70JCS(C)800). 

Figure 5.21 Reaction of enol ethers with glycosidases For references to the reactions depicted see text, for GH 2 lacZ enzyme Refs. 110 and 111, for hydration of exocyclic gluco compound Refs. 112 and 113 and reaction of cellobial Ref. 114.

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. 

The metabolite of 2-amino-4-phenylthiazole (used as an anaesthetic for fish) was identified (223) as 2-amino-4-phenylthiazole 2-N, -d-glucopyranosiduronic acid (71) (Scheme 50). The formation of this compound probably involves the reaction of the exocyclic nitrogen on the Open-chain form of the acid. The isolation of this metabolite is part of a very Systematic study by Japanese researchers related to the anaesthetic... 

Butler recently reviewed the diazotization of heterocyclic amines (317). Reactions with nitrous acid yield in most cases N-exocyclic compounds. Since tertiary amines are usually regarded as inen to nitrosation, this... 

Bromination of 2-dialkylaminothiazoles has been reported to be successful by one author (415) and to fail by others (375. 385). If the mechanism of direct electrophilic substitution is accepted for these compounds, it is difficult to understand why alkyl substitution on such a remote position as exocyclic nitrogen may inhibit this reaction in the C-5 position. 

The principal reactions of this class of compounds are summarized in Scheme 172. In most of these reactions the reactive nucleophilic center is the terminal NHj group, although the other exocyclic nitrogen may also be involved, as shown by acetylation, which yields 284 and 285. However, the structure of compound 281 is not the one proposed in a recent report (1582) that attributes the attack to the other exocyclic nitrogen. The formation of osazones (287) from sugars, 2-hydrazinothiazoles, and hydrazine has been reported (525, 531). 

Imino-4-thiazolines are far more basic than their isomeric 2-aminothiazoles (see Table VI-1). They react with most electrophDic centers through the exocyclic nitrogen and are easily acylated (37, 477, 706) and sulfonated (652). The reaction of 2-imino-3-methyi-4-thiazoline (378) with a-chloracetic anhydride yields 379 (Scheme 217) (707). This exclusive reactivity of the exocyclic nitrogen precludes the direct synthesis of endocyclic quaternary salts of 2-imino-4-thiazolines. although this class of compounds was prepared recently according to Scheme 218 (493). 

Nucleophilic reactivity of the sulfur atom has received most attention. When neutral or very acidic medium is used, the nucleophilic reactivity occurs through the exocyclic sulfur atom. Kinetic studies (110) measure this nucleophilicity- towards methyl iodide for various 3-methyl-A-4-thiazoline-2-thiones. Rate constants are 200 times greater for these compounds than for the isomeric 2-(methylthio)thiazole. Thus 3-(2-pyridyl)-A-4-thiazoline-2-thione reacts at sulfur with methyl iodide (111). Methyl substitution on the ring doubles the rate constant. This high reactivity at sulfur means that, even when an amino (112, 113) or imino group (114) occupies the 5-position of the ring, alkylation takes place on sulfiu. For the same reason, 2-acetonyi derivatives are sometimes observed as by-products in the heterocyclization reaction of dithiocarba-mates with a-haloketones (115, 116). 

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%. 

However, exo-selective Diels-Alder reactions are found when a,/J-unsatu-rated exocyclic carbene complexes are used as dienophiles. The fixed s-cis conformation of the vinylcarbene moiety of the complex seems to be responsible for the exo selectivity observed in this reaction. Moreover, the reaction of optically active carbene complexes with 2-morpholino- 1,3-butadienes allows the asymmetric synthesis of spiro compounds [99] (Scheme 53). 

The principle of active-site-directed inactivation of glycosidases by gly-con-related epoxides can be extended to compounds having an exocyclic oxirane ring, either directly attached to the six-membered ring (32) or at some distance (33,34). Studies with -o-glucosidase from sweet almonds and intestinal sucrase-isomaltase revealed that, in spite of the higher intrinsic reactivity of these epoxides, this shift of the position of the epoxide function causes a 10- to 30-fold decrease of kj(max)/Ki, an effect which probably reflects the limited flexibility of the catalytic groups involved in the epoxide reaction. 

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. 

In addition to monomer III two major by products (IV) and (V) were detected (18). Compound (IV) was a dimer which resulted from Diels-Alder reaction between two exocyclic dienes (III) and was found at the bottom of the sublimator after thermal decomposition of the sulfone II. The GC/mass spectrum of this sample showed a molecular ion peak of 342 m/e that was in agreement with dimer molecular weight. The compound (V) had a pink tint and was found in a trace quantity in the crude N-pheny1-3,4-dimethylenepyrrolidine (III) by NMR (6 1.9 - 1.8, -CH, s). It could also be readily formed when N-pheny1-3,4-dimethyrenepyrrolidine (III) solution was exposed to air for a period of time. 

A similar sequence starting with the acylation product (76) from metachlorophenylacetonitrile gives the halogenated tricyclic ketone 83. Condensation of that intermediate with ethyl bromoacetate in the presence of zinc (Reformatsky reaction) gives the hydroxyester 84. This product is then in turn dehydrated under acid conditions (85), saponified to the corresponding acid (86), and converted to the dimethyl-amide (87) by way of the acid chloride. The amide function is then reduced to the amine (88) with lithium aluminum hydride catalytic hydrogenation of the exocyclic double bond completes the synthesis of closiramine (89). This compound also exhibits antihistaminic activity. 

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