Gurpreet
Singh
and
Jeffrey
Aubé‡
*
The University of Kansas Chemical Methodologies and Library Development Center, 2034 Becker Drive, Del Shankel Structural Biology Center, Lawrence, Kansas 66047, United States. E-mail: jaube@unc.edu
First published on 12th April 2016
A useful design element in small molecule libraries is spatial diversity, in which binding moieties are systematically directed toward different regions of three-dimensional space. One way of achieving this is through the use of conformationally diverse scaffolds onto which various binding moieties can be placed. Such scaffolds can represent synthetic challenges of their own. In this paper, we describe a new route to chiral, cyclic 1,3-diol building blocks that features silylated dithianes as relay linchpins. These diols are subsequently used for the construction of a 24-compound pilot library bearing two amino acid residues.
Although early combinatorial libraries were based on peptides and therefore intrinsically stereochemically rich, the development of the next generation of libraries depended strongly on available chemistry suitable for parallel synthesis, which often led to an over-emphasis on achiral compounds.2 Subsequently, various approaches to creating libraries with a strong emphasis on stereochemical diversity have appeared. One is to use chiral natural product templates, which more often than not are generated from naturally occurring sources.3 For fully synthetic libraries constructed under the rubric of diversity-oriented synthesis, the use of chiral building blocks is a hallmark of strategies such as “build/couple/pair”,4 “click/click/cyclize”,5 and by systematically varying the configuration and hybridization of a key stereocenter.6
Recently, we published an approach toward small-molecule libraries based on the stereochemical and conformational diversification of a piperidine template (Fig. 1).7 In this work, 1,3-allylic strain was used both to control substitution patterns in the central ring and to impose a degree of conformational diversity on the final products. In this paper, we disclose a simpler approach in which 1,3-diols attached to 5- and 6-membered rings serve as attachment points for chemical diversity (here, amino acid-based substituents) and the standard conformational tendencies of the rings are used to provide a modest degree of conformational flexibility (Fig. 1b). For example, substituents are displayed via dramatically different vectors when attached to cis vs. trans 1,3-disubstituted cyclopentenes; a further degree of diversity is obtained from the conformational mobility of rings having particular substitution patterns.
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Fig. 1 (a) Use of 1,3-allylic strain to establish conformational diversity in a small molecule library.7 (b) This work: conformational diversity encouraged by placing groups onto cyclic 1,3-diols. |
These rings also permit the incorporation of additional diversity elements. For example, the presence of a double bond in the cyclopentene-based scaffold serves as a potential site for additional hydroxyl groups or transformation into acyclic scaffolds using ring-opening metathesis, while the 6-membered rings can be substituted by carbon, sulfur, or nitrogen, the last of which is a natural site for substitution as well. In this paper, we describe (1) the synthesis of diols suitable for the display of binding moieties, including a new route to chiral, cyclic 1,3-diol building blocks of general utility in synthesis and (2) the construction of a pilot library that displays two amino acid residues through these linkers.
Although cyclohexane-1,-3-diols have been used as precursors in the syntheses of biologically important natural products and pharmaceutically important compounds,10 most of their reported syntheses result in moderate yield and selectivities.11 Enantioenriched synthesis of these diols has also been targeted by different groups however involve multi-step synthesis and one or more enzymatic desymmetrization steps.12 Similarly, there are only a few approaches to the synthesis of 3,5-dihydroxy piperidines. In 2006, Cossy reported a synthesis of enantioenriched 3,5-dihydroxy piperidine via ring-expansion of 4-hydroxyproline,13 and Bäckvall reported a combined enzymatic/metallocatalysis route to related materials.14
We considered that one convenient approach would be to subject compound 115 to dual displacement of the two chlorine atoms by a one-atom, doubly-activated, nucleophile (Fig. 2). A clue for accomplishing this was provided by the work of Linclau, who used a dithiane-based linchpin for the preparation of carbonucleosides.16 Such relay approaches have been largely popularized by Smith,17 (who used this chemistry for the preparation of piperidines in a diversity-oriented synthesis context18). The primary challenge in adapting this route to our present purpose was to subvert the dominant regiochemistry of the Linclau route, which proceeded according to the Baldwin paradigm to afford a five-membered ring with >10
:
1 selectivity.19 We felt that this would be possible were we able to prevent epoxide formation prior to the second nucleophilic (i.e., cyclization) attack, which we anticipated accomplishing through protection. Success also depended upon the initial attack occurring at the epoxide and not the chloride atom.
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Fig. 2 (a) Plan for making chiral six-membered ring trans diols. (b) Linclau's route to chiral cyclopentanes using a dithiane linchpin approach.16 (c) Proposed modification to direct the relay route toward six-membered ring formation. |
This plan worked as expected (Scheme 2). Addition of 1 equiv. of n-BuLi to a precooled solution of dichlorodiol (R,R)-1 in THF followed by the addition of 1 equiv. of TIPSCl yielded the mono silylated product 4; interestingly, no epoxide formation was observed under these conditions. The remaining chlorohydrin was converted to epoxide in excellent yield using powdered potassium hydroxide in anhydrous diethyl ether. Lithiation of 2-TBS-dithiane was carried out at room temperature in a 9:
1 mixture of THF/HMPA using n-BuLi as base. The resulting yellow solution was added to a pre-cooled solution of the epoxide (1R,3R)-5 in 9
:
1 THF/HMPA at −78 °C. The reaction mixture was maintained at −78 °C for 0.5 h and then raised to −40 °C for 2 h. Consumption of the starting material was observed by TLC at −40 °C, indicating opening of the epoxide. Further allowing the reaction to stir at rt for 18 h formed the cyclized product 6 in 88% yield. The disilyl cyclohexanediol (8R,10R)-6 was treated with 1 M TBAF in THF to produce C2-symmetric 1,3-cyclohexanediol (R,R)-7 in 94% yield.
A similar protocol was applied to afford mono-protected diols by replacing the linchpin reagent with TMS-dithiane and selective removal of the more labile TMS ether, which occurred spontaneously upon conversion of 8 to either alkane 9 or ketone 10 (Scheme 3). Having previously encountered unexpected difficulties in monosilylation of symmetrical diols,9 this was viewed as an attractive entry into these monoprotected building blocks for library synthesis. As demanded by parity conservation, application of these reaction sequence beginning with (S,S)-1 led to the enantiomers of these building blocks (not shown).
Application of the above strategy to heterocycles synthesis did not require formation and isolation of a precursor epoxide (although it is very likely that one is formed in situ), but did benefit from conversion of the dichloride bis-electrophile to the corresponding diiodide and carrying out the reactions at ca. 100 °C in EtOH for 16 h. As shown in Scheme 4, enantiopure monoprotected or unprotected 3,5-dihydroxypiperidines and -thianes were obtained from common intermediates 4. As above, either enantiomeric series may be obtained in this way.
Following some experimentation, it was determined that the best route for conversion of the open alcohol to a carbamate was via a p-nitro carbonate, which was readily synthesized as shown in Scheme 5. Thereafter, 16 was treated with a set of amino acid esters in the presence of catalytic amount of DMAP in THF at 100 °C to afford 17a–d in 79–83% yield. These carbamates were isolated on 600–700 mg scale and fully characterized.
The silyl carbamates 17 were deprotected using TBAF and the resulting crude alcohols treated with amino acid isocyanate. Initial attempts, in which isocyanate was reacted with alcohol in refluxing toluene for 48 h, were very slow and left a significant amount of starting material. Ultimately, reacting alcohols with excess of neat isocyanates (3 equiv.) in the presence of catalytic amount of N,N-dimethylaminopyridine at 100 °C led to successful completion of the reactions. To complete the construction of this demonstration library, alcohols 17a–d were reacted with six different amino acid isocyanates in two-dram vials on a 24-well heating block. The reaction mixture was cooled to room temperature and was dissolved in dichloromethane. The crude reaction mixtures were subjected to solid-phase extraction to remove unreacted isocyanates followed by mass-directed automated purification, resulting in 18 biscarbamates in 5–71 mg quantities and purities of >90%. The purification results of the 24 compounds are listed in the Table 1. No obvious trends regarding success in this library format are evident from these results.
Entry | Compound | R1 | R2 | Amount (mg) | Purity (%) |
---|---|---|---|---|---|
1 | 18a | 3-Indolyl-ylmethyl | PhCH2 | 24 | 100 |
2 | 18b | 3-Indolyl-ylmethyl | t BuOCH2 | 62 | 98 |
3 | 18c | 3-Indolyl-ylmethyl | (CH3)2CHCH2 | 34 | 94 |
4 | 18d | 3-Indolyl-ylmethyl | CH3SCH2CH2 | 25 | 79 |
5 | 18e | 3-Indolyl-ylmethyl | t BuO2CCH2CH2 | 54 | 99 |
6 | 18f | 3-Indolyl-ylmethyl | p-tBuOPhCH2 | 25 | 92 |
7 | 18g | H2NCOCH2 | PhCH2 | 27 | 100 |
8 | 18h | H2NCOCH2 | t BuOCH2 | 44 | 98 |
9 | 18i | H2NCOCH2 | (CH3)2CHCH2 | 39 | 39 |
10 | 18j | H2NCOCH2 | CH3SCH2CH2 | 26 | 100 |
11 | 18k | H2NCOCH2 | t BuO2CCH2CH2 | 66 | 98 |
12 | 18l | H2NCOCH2 | p-tBuOPhCH2 | 22 | 39 |
13 | 18m | L-Proline | PhCH2 | 34 | 100 |
14 | 18n | L-Proline | t BuOCH2 | 10 | 98 |
15 | 18o | L-Proline | (CH3)2CHCH2 | 18 | 97 |
16 | 18p | L-Proline | CH3SCH2CH2 | 71 | 100 |
17 | 18q | L-Proline | t BuO2CCH2CH2 | 25 | 56 |
18 | 18r | L-Proline | p-tBuOPhCH2 | 34 | 98 |
19 | 18s | CH3 | PhCH2 | 5 | 78 |
20 | 18t | CH3 | t BuOCH2 | 27 | 96 |
21 | 18u | CH3 | (CH3)2CHCH2 | 29 | 41 |
22 | 18v | CH3 | CH3SCH2CH2 | 39 | 98 |
23 | 18w | CH3 | t BuO2CCH2CH2 | 33 | 92 |
24 | 18x | CH3 | p-tBuOPhCH2 | 38 | 65 |
Finally, a few examples of C2-symmetrical analogs were created directly from the corresponding fully unprotected diols (Scheme 6). Thus 19 was synthesized directly from (S,S)-2 using ring-closing metathesis and 20 by deprotecting (1S,3S)-9, and (S,S)-13 and (S,S)-15 as shown in Scheme 4. Individual diols were then directly reacted with 3 equiv. of isocyanate to afford the depicted derivatives in moderate yields following chromatography.
Footnotes |
† Electronic supplementary information (ESI) available: Experimental details, compound characterization, spectra, and chromatographs of selected compounds. See DOI: 10.1039/c6ob00598e |
‡ Current address: UNC Eshelman School of Pharmacy, 125 Mason Farm Road, CB 7363, University of North Carolina, NC, 27517 USA. |
This journal is © The Royal Society of Chemistry 2016 |