Short Synthesis of Orthogonally Protected 3α,12α‐Diamino‐5β‐cholan‐24‐oic Acid, a Dipodal Steroid Scaffold for Combinatorial Chemistry

Abstract

A short, practical, multigram-scale synthesis of C3α-NHAlloc, C12α-NHBoc-diamino-5β-cholan-24-oic acid 2 was developed, applying a new, straightforward synthetic strategy. Key features are the conservation of the carboxyl moiety at C24 during oxime reduction, the late differentiation between the C3 and C12 amino groups and the gradual separa- IntroductionThe steroid core has proven to be a versatile building block for the design of frameworks capable of ionic [1] and molecular recognition, [2] the preparation of antimicrobial agents [3] and novel amphiphiles. [4] Bile acid based systems can be further important in the understanding of the functioning of natural systems. Moreover, steroids have found extensive application as scaffold for the assembly of combinatorial libraries.[5] Therefore research on bile acids, their derivatives and potential applications is actively pursued. [6] In order to attain these goals and to broaden the plethora of possible applications, a fast, easy and efficient access to these steroid building blocks is needed. Our earlier efforts in the area concerned the construction of heterodipodal peptidosteroid libraries of potential serine protease mimics and were based on the use of the C3α-NHAlloc-, C7α-OAc-, C12α-NHBoc-protected diamino steroid scaffold 1 (Figure 1). The synthesis of suitable quantities of scaffold starting material was a difficult and time-consuming task.[7] Starting [a]

Shortcut Access to Peptidosteroid Conjugates: Building Blocks for Solid-Phase Bile Acid Scaffold Decoration by Convergent Ligation

“…Whereas the strategy described above used building block 3 synthesized by Davis et al . in 11 (multi-stage) steps from cholic acid ( 1 ), the simpler version 4 ( Figure 1 ) of this essentially dipodal scaffold has been obtained in our group starting from deoxycholic acid ( 2 ) through an ultra short 6-step synthetic route [ 25 ].…”

“…Therefore, in recent years, emphasis has been put on the replacement of the hydroxyl by amino functionalities, with tripodal scaffold 3 and dipodal counterpart 4 as state-of-the art members reported by Davis et al . [ 24 ] and our group [ 25 , 26 ], respectively. The amino groups are readily convertible into stable linkages, most often amides, and allow for reliable elaboration on solid supports.…”

LC-(TIC/EIC)-MS as tool in the analysis of diastereomeric 3,12-aza-analogues of deoxycholic acid

“…To efficiently obtain sufficient quantities of scaffold material in a short time period, we conceived a new synthetic route, applying a very straightforward strategy. 1 Whereas previously published routes for similar scaffolds require a large number of synthetic steps (usually >10), 2 we were able to significantly limit the number of steps to only six. In contrast to the commonly used sequential derivatization of the hydroxyl functions, necessary to guarantee the correct stereochemistry and differentiation of the different positions, we proceeded via the simultaneous transformation of these functions to the corresponding diamine.…”

Untapped Opportunities of Resin‐to‐Resin Transfer Reactions (RRTR) for the Convergent Assembly of Multivalent Peptide Conjugates

“…Depicted in Figure A, our proof‐of‐concept design comprised a bile acid based steroid scaffold as the accepting template, and a transcription factor derived model peptide . Shuttled from the donor resin ( 1 ), the selected sequence features a representative variety of amino acid residues and side‐chain protecting groups.…”

“…Excesses of solution-phase speciesa re easily removed after reactionb ys imple filtration and washing of the resin mixture.I ntermediatem onitoring andf inal isolation is possible after cleavage of the (sampled) beads, cleanly done through mild UV irradiation. [54] Depictedi nF igure2A, our proof-of-concept designc omprised ab ile acid based steroids caffold as the accepting template, [55,56] and at ranscription factor derived modelp ep-tide. [57,58] Shuttled from the donor resin (1), the selected sequencefeatures arepresentative variety of amino acid residues and side-chain protecting groups.A tt he acceptorr esin (2), paminomethyl benzoic acid (PAMBA) was installed betweent he photocleavable linker and the available C24-position of the bile acid moiety,a sm onitoring tag for reaction at the UV-inactive steroid.…”