Isopropyl functional moietie

Thiazoles are less electron-rich isosteres of pyridines and therefore it was speculated that compounds with such substitution may have improved metabolic stability [30]. The modeling of A-82200 in which the N-terminal pyridinyl group was substituted by a 4-thiazolyl moiety indicated that the 5-membered ring binds in the S3 subsite and can be further derivatized at the 2 position by an isopropyl group. The isopropyl functionality makes van der Waals contacts with Val82 and fills the hydrophobic part of the S3 subsite in nearly optimal fashion. 

Work in the pyrone series delineated the beneficial effect of substituting ortho to the sulfur linkage on the S-phenyl with an isopropyl moiety. Modeling of the ortho isopropyl functional group with the 5,6-dihyropy-rone template indicated that it probably filled the S, pocket This observation led to modifications of the initial dihydropyrone lead, resulting in agents with improved enzyme potency (Table 7). 

It has been stated earlier that the first generation and the second generation P-blockers essentially possess either isopropyl or tertiary-huiyX functional moieties attached to the N-alkyl groups. 

We explain the selective formation of diastereomer 52 on the basis of conformational arguments. The two likely conformers of 50 should have an essentially planar allyl moiety, whereas the six-membered ring should exist in two quasi-chair conformers with either the isopropyl or the methoxy group in the quasi-axial position. The conformer with the (bulkier) isopropyl group in a quasi-equatorial position is preferred. While access to the terminal allylic carbon (which leads to 51) appears to be unhindered, the quasi-axial substituent at the chiral carbon will interfere with the attack on the internal allylic center, directing the attack to the face opposite to the quasi-axial methoxy function, (- 52). These considerations account for the preference of 51 over 52 as well as for the suppression of the diastereomer. 

Dioxazoles 146 are readily prepared by transketalization of 2,2-diethoxypropane, where both the NH and OH moieties are protected in a non-protic form (Scheme 68). The dioxazoles 146 are stable to a wide variety of reaction conditions and readily revert back to the hydroxamic acids 145 and isopropyl ester 147 (145/147 50/1) by treatment with Nafion-H in 2-propanol. The method is applicable to primary, secondary, tertiary and aromatic hydroxamic acids, and the acidity of the protons adjacent to the dioxazole allows R-functionalization. 

Extensive theoretical and empirical work (17) has shown that the isopropyl group is identifiable by (1) split symmetrical carbon-hydrogen deformations at 1382.5 2.5 and 1367.5 2.5 cm"1 and (2) by two skeletal vibrations. One of these vibrations occurs at a remarkably constant frequency of 1168.5 1.5 cm"1, whereas the frequency of the other vibration decreases as a function of the molecular weight (MW) of the rest of the molecule, from 1170 cm"1 for MW 15 (methyl group) to 1142 cm"1 for MW 99 (heptyl group). For an attached moiety of MW 259, as in abietic acid, the band whose frequency depends on the molecular weight of the rest of the molecule is found at still lower wavenumbers. 

The success of cycloisomerization reactions of this type is critically dependent on factors that influence the conformational mobility of the side chain bearing the alkene moiety. Additionally, functional groups which are able to serve as ligands at palladium may also be of importance. As an example, neither the (E)- nor the (Z)-crotonate derivative ( -IS or (Z)-13 gives rise to the formation of bicyclic products on treatment with bis(dibenzylideneacetone)palladium/tri-isopropyl phosphite. Instead, the corresponding isomeric substituted butadienes, methyl (2E or 2Z,6 )-7,8-dimethylnona-2,6,8-trienoate (14) and methyl (2E or 2Z)-8-methyl-7-methyl-enenona-2,8-dienoate (15), are formed. 

Our initial approach centered on the use of a strategic Wessely oxidation reaction to transform an appropriately decorated resorcinol precursor into a tricyclic cage architecture formed by an in situ intramolecular Diels-Alder cycloaddition reaction (Scheme 1). From there we envisioned a 6-exo-type cyclization to form the tetracyclic core, which in the best case scenario would also set the C9-methyl stereocenter. Manipulation of the functional groups on the tetracyclic core would then be followed by a late-stage C—C bond fragmentation reaction to access the vinigrol core. Conversion of the exocyclic methyl ketone group was expected to afford the desired isopropyl moiety. 

Miyabe and Naito revealed a synthesis of y-lactones through sequential radical reaction of acrylates bearing oxime functionality with alkyl radicals generated from iodoalkane and efliyl radical [62]. That is, addition reaction of isopropyl radical to acrylate moiety of substrate 86 and the following cyclization to oxime functionality produced the p-amino-y-butanolide 87 with good diastereoselectivitiy (Scheme 40). 

Sasai et al developed a bifunctional BINOL-derived organocatalyst (37) and reported an aza Morita-Baylis-Hillman reaction (Scheme 2.80) [148]. While the 3-pyridyl moiety functioned as a Lewis basic site, the diol moiety worked as a Bronsted acidic site. It is noted that introduction of N-isopropyl-N-3-pyridinylaminomethyl moiety at the 3-position is essential for attaining excellent enantioselectivity. They subsequently introduced 2-diphenylphosphinophenyl group onto the third position and successfully utilized it in the aza Morita-Baylis-Hillman reaction [149]. 

Dendrobine, a congener of the powerful convulsant picrotoxinin, was first isolated from the Chinese tonic Chin Shih Hu in 1932, but its complete structure was not unravelled until 1964. Three groups of workers have reported the synthesis of dedrobine since that time. The synthesis outlined below was developed by Kende and his group at Rochester, and is based on the c/s-hydroindan nucleus (B) derived from the Diels-Alder adduct (A) by cleavage and aldol cyclization. The hydroindan derivative (B) already carrying the isopropyl unit, bears appropriate functionality for elaboration of the N-methylpyrrolidine ring and the 7-lactone moiety. 

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