Methylation of cycloamyloses (cyclodextrins) has been used to obtain derivatives of improved characteristics for application in pharmacy' and chromatographyzV3. Well established procedures for several methylated cycloamyloses are in use. For example, the Kuhn-Trischmann procedure uses Ba(OH), as a base and Me,SO and N,Ndimethylformamide (DMF) as solvents and yields products in which primarily the C-2 and C-6 hydroxyl groups are methylated4*. The Hakomori and Brimacombe procedures produce fully methylated derivatives of cycloamyloses; in these procedures Me,SO or DMF are used as solvents and cycloamyloses are fully converted into their alkoxide forms"'. Recently, heptakis(20methyl)cyclomaltohept&se has also become accessible by a procedure analogous to Hakomori methylation but in which the carbohydrate was only partially converted into the alkoxide form12.
Analysis of the course of methylation of cycloamyloses should be helpful in understanding the effects of reaction conditions on the relative reactivities of the three hydroxyl groups at C-2, C-3, and C-6. Here, the course of methylation of three cycloamyloses, namely cyclomaltohexaose, cyclomaltoheptaose, and cyclomaltooctaose, under Hakomori conditions, that is, with an excess of base in Me,SO, was investigated and the results compared with the course of methylation using limited base concentration in the same solvent as described" while our work was in progress.
To analyze the course of methylation, a very simple process involving 13C-n.m.r. spectroscopy was used. A pulse of highly enriched (99O/,) 13C-labelled methyl iodide was introduced at four different stages of the Hakomori procedure performed with an excess of base (3.7 mol per mol of glucose residues of the cycloamylose) and unlabeled methyl iodide containing only 1.1% of '3C-isotope (5.2 mol per mol of glucose residues of the cycloamylose), compare Table I andExperimental section. Fully methylated cycloamyloses were then isolated and the positions and extent to which the 13C-methyl groups were incorporated was established by measurement of 13C-n.m.r. spectra. The peaks of the three methyl carbons at O-2,0-3, and O-6 are readily distinguished in the 13C-n.m.r. spectra and have been unambiguously attributed previously'3x'4. Introducing a pulse of "C-labeled methyl iodide at a particular stage during the course of the reaction, and simply measuring the relative intensities of the 2-0,3-O, and 6-O-methyl carbons in the