COMMUNICATIONS 1962  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 1433-7851/01/4010-1962 $ 17.50+.50/0 Angew. Chem. Int. Ed. 2001, 40, No. 10 Synthesis of Cored Dendrimers with Internal Cross-Links** Laura G. Schultz, Yan Zhao, and Steven C. Zimmerman* The physical properties of a dendrimer may be manipulated by post-synthetic modification of its periphery, core, or interior. Such alterations can tune the bulk properties of the dendritic system and frequently convert simple dendrimers into functional macromolecules. For example, incorporation of molecular recognition elements on the periphery of a dendrimer produces multivalent receptors capable of ligand binding or supramolecular assembly. [1] Organometallic func- tional groups can also be added to the periphery, thus creating macromolecular catalysts. [1±3] In contrast to the many reports of end-group functionalization, there are only a few examples of covalent modification of the interior of the dendrimer. [4] We recently reported [5] the ªcoringº of dendrimer 1 by ring- closing metathesis (RCM) of the peripheral homoallyl ether groups [6] using ruthenium benzylidene catalyst 2 [7] followed by hydrolytic removal of the core. In some respects, ªcoredº dendrimers resemble hollow, polymeric nanospheres or core- shell nanoparticles. [8] Consequently, the potential of ªcoredº dendrimers to encapsulate or complex substances makes them outstanding candidates for delivery agents or molecular sensors. Our reported synthesis of cored dendrimers [5] is limited in its scalability by the requirement of high dilution (about the partial separation of the pure diastereomers, which were obtained in a combined yield of 75 %. Removal of the protecting groups with trimethyl- silyl triflate, [19] N-acylation with octanoyl chloride [20] and final chromatog- raphy afforded erythro-1 in 14 % overall yield from pentadecyne. erythro-1:[a] D  3.0 (c  0.8 in CHCl 3 ); IR (NaCl): n Ä  1550, 1644, 3010, 3287 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): d  0.87 (t, 6 H, J  6.2 Hz), 1.01 (s, 2H), 1.25 (s, 28H), 1.60 (m, 4H), 2.24 (t, 2H, J  7.2 Hz), 2.45 (dt, 2H, J  7.6, J'  1.2 Hz), 3.02 (br s, 1H), 3.37 (br s, 1H), 3.71 (dd, 1H, J  11.4, J'  3.4 Hz), 3.87 (dd, 1 H, J  11.2, J'  4 Hz), 4.18 (m, 1H), 4.85 (s, 1 H), 6.37 (br d, 1 H) ; 13 C NMR (75 MHz, CDCl 3 ): d  8.36, 14.04, 14.10, 22.58, 22.66, 25.70, 25.82, 27.27, 28.99, 29.19, 29.33, 29.37, 29.44, 29.57, 29.63, 29.64, 29.64, 29.67, 31.65, 31.89, 36.77, 53.74, 63.12, 70.52, 107.52, 115.40, 174.00. HR-MS calcd for C 27 H 51 NO 3 : 437.386895; found: 437.387000. The dihydroceramide desaturase inhibition assay was performed by using rat liver microsomes, which were prepared as reported. [5] The activity of dihydroceramide desaturase was determined in phosphate buffer (0.1m, pH 7.4), with d-erythro-N-octanoylsphingosine as substrate. The inhibitor (at the indicated concentrations) and the substrate (15 nmol) were solubilized (15 nmol of BSA in phosphate buffer/ethanol 9:1 v/v, 100 mL), combined with the microsome suspension (1 mg of protein) and NADH (30 mL, 1 mm in phosphate buffer), and made up to a final volume of 300 mL with phosphate buffer. The suspension was incubated for 30 min at 37 8C, and the reactions were terminated by the addition of CHCl 3 (0.5 mL) containing d-erythro-N-hexanoylsphingosine (1 nmol) as an internal stan- dard for quantification. The lipids were extracted with CHCl 3 (2  250 mL), the combined organic layers were evaporated under a stream of nitrogen, and the residue was derivatized with bistrimethylsilyltrifluoroacetamide (50 mL, 25 8C, 60 min). After derivatization, CHCl 3 (50 mL) was added and the samples were stored at  80 8C. Instrumental analyses were carried out by gas chromatography coupled to electron impact (70 eV) mass spec- trometry using a Fisons gas chromatograph (8000 series) coupled to a Fisons MD-800 mass-selective detector. The system was equipped with a nonpolar Hewlett ± Packard HP-1 capillary column (30 m  0.20 mm i.d.), which was programmed from 100 8C to 340 8C at 7 8C min 1 . Analyses were carried out in the selected ion monitoring mode. Selected ions were m/z  311, 313, 230, and 258. Dwell (time for which a given mass is monitored) was set at 0.02 s and the mass span at 0.5. Received: January 31, 2001 Revised: March 8, 2001 [Z 16535] [1] T. Kolter, K. Sandhoff, Angew. 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Org. Chem. 1990, 55, 870 ± 876. [20] P. De Ceuster,G. P. Mannaerts, P. P. Van Veldhoven, Biochem. J. 1995, 311, 139 ± 146. [21] K. Raith, J. Darius, R. H. Neubert, J. Chromatogr. A 2000, 876, 229 ± 233. [22] The activities of dihydroceramide desaturase were 1.4  0.3 nmol h 1 mg 1 in microsomes incubated with threo-1 and 1.3  0.2 nmol h 1 mg 1 in control microsomes (average  standard devia- tion, n  3). [23] R. H. Unger, L. Orci, Int. J. Obes. 2000, 24(Suppl. 4), S28 ± S32. [*] Prof. S. C. Zimmerman, L.G. Schultz, Y. Zhao Department of Chemistry University of Illinois 600 S. Mathews Ave., Urbana, IL 61801 (USA) Fax: ( 1) 217-244-9919 E-mail : sczimmer@uiuc.edu [**] This work was supported by the National Institute of Health (GM 39782). L.G.S. acknowledges the Department of Chemistry, University of Illinois, and Pharmacia & Upjohn for fellowship support. Supporting information for this article is available on the WWW under http://www.angewandte.com or from the author.