CSIRO PUBLISHING Full Paper www.publish.csiro.au/journals/ajc Aust. J. Chem. 2010, 63, 693–699 Orthogonally Protected Monosaccharide Building Blocks for Solid Phase Production of Diversity Oriented Libraries Premraj Rajaratnam, A Praveer Gupta, A Peter Katavic, A Krystle Kuipers, A Ngoc Huyh, A Sarah Ryan, A Tania Falzun, A Gerrald B. Tometzki, A Laurent Bornaghi, A Giang Le Thanh, A Giovanni Abbenante, A Ligong Liu, A Wim Meutermans, A Norbert Wimmer, A and Michael L. West A,B A Alchemia Limited, 3 Hi Tech Court, Eight Mile Plains, Brisbane, Qld 4113, Australia. B Corresponding author. Email: mwest@alchemia.com.au The large scale synthesis of three orthogonally protected monosaccharide scaffolds suitable for use in the solid phase preparation of large diversity libraries is presented. Scaffolds based on 2-amino-2-deoxy-d-glucopyranose, 2-amino-2- deoxy-d-allopyranose, and 2,4-diamino-2,4-dideoxy-d-galactopyranose were prepared in good yield and with minimal chromatographic purification from commercially available methyl 2-azido-2-deoxy-1-thio-β-d-glucopyranose and methyl 2-amino-2-deoxy-1-thio-β-d-glucopyranose. Manuscript received: 9 September 2009. Manuscript accepted: 4 January 2010. Introduction With five functionalized chiral centres in a cyclic arrange- ment, monosaccharides represent versatile and compact scaf- folds that provide the medicinal chemist plenty of scope to custom design molecules to a pharmacophore model. [1,2] Highly diverse molecules can be envisaged and new bioactives identi- fied by appending suitable substituents at various positions on the monosaccharide scaffold. [3–6] For close to 20 years, this has been explored by many laboratories and that work is well reviewed. [7,8] We have been interested in employing the sugar scaffold to produce libraries of systematic diversity. [9] In order to produce such libraries, the need for a series of orthogonally protected monosaccharide scaffolds was identified. It was apparent that these building blocks must be readily synthesized at the 100 g scale with potential to be prepared at the kilogram scale. The building blocks needed to be protected with groups that are stable to the wide variety of chemical conditions required to introduce and elaborate the substituent groups. Here we report the design and large scale synthesis of three such building blocks based on d-glucopyranose, d-allopyranose, and d-galactopyranose, that we have successfully used as the starting points in the production of our diversity oriented libraries. [10] Results and Discussion Building Block Design and Synthesis It was anticipated that a series of large diversity libraries would be prepared from a small number of orthogonally protected monosaccharide scaffolds. Efficient production of these libraries required a solid phase approach necessitating one resin attach- ment position on the carbohydrate building block. The choice of the attachment position was governed by several other requi- site characteristics of the target molecules within the library. The anomeric position in the target libraries always bears a substituent in order to prevent hemiacetal anomers and poten- tial chain opening configurations of the final products, thus precluding the use of the anomeric position as a suitable attach- ment point to resin. An amino group at the C-2 position was used as this simplified the selection of the orthogonal pro- tecting groups for the scaffold. The scaffolds were designed with the intention that the C-2 amine in the final products of the library would be substituted with groups such as acyl or carbamoyl moieties that restricted the rotation of the appended groups. Consequently, the C-2 position was unsuitable for attach- ment to the solid support. The C-3 and C-6 positions can be readily protected in a selective manner, leaving the least reactive position C-4 on 2-amino-2-deoxy-d-glucopyranose and 2-amino-2-deoxy-d-allopyranose, which was used as the resin attachment point for orthogonally protected building blocks based on these monosaccharide scaffolds. The protecting groups, outlined in Table 1, were selected for the 2-amino-2-deoxy- d-glucopyranose and 2-amino-2-deoxy-d-allopyranose building blocks, to allow regio-specific introduction of a wide vari- ety of substituents. The thiomethyl glycoside [11] at C-1 allows direct introduction of a wide variety of substituents through glycosidation of a range of alcohols in solution phase before resin-loading. A third monosaccharide scaffold was based on a 2,4-diamino- 2,4-dideoxy-d-galactopyranose core. This scaffold contained a masked axial C-4-amino group and a protected equatorial C-2 amino group resulting in a building block containing two nitrogen atoms. The protecting groups selected for this building block were a thiomethyl glycoside for C-1, a 5 ′ -methylene-1 ′ ,3 ′ - dimethypyrimidine-2,4,6-(1H,3H,5H )trione (DTPM) for C-2, a benzoate ester for C-3, and an azide for C-4, with a masked resin- linking position at C-6 (Table 2). The resin linking position in the scaffold is masked with a tert -butyldiphenylsilyl ether to © CSIRO 2010 10.1071/CH09480 0004-9425/10/040693