Method Article

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

DOI:

10.3791/58508

⸱

February 6th, 2019

 ,  , 
1Department of Biology and Chemistry, Azusa Pacific University

In This Article

Summary

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Here we present a protocol to demonstrate an efficient method for the synthesis of spirocyclic heterocycles. The five-step process utilizes solid-phase synthesis and regenerating Michael linker strategies. Generally difficult to synthesize, we present a customizable method for the synthesis of spirocyclic molecules otherwise inaccessible to other modern approaches.

Abstract

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A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule's potential use in biological systems. By means of solid-phase synthesis, regenerating Michael (REM) linker strategies, and 1,3-dipolar cycloaddition, a library of structurally similar heterocycles, both with and without a spirocyclic center, can be constructed. The main advantages of the solid-support synthesis are as follows: first, each reaction step can be driven to completion using a large excess of reagents resulting in high yields; next, the use of commercially available starting materials and reagents keep the costs low; finally, the reaction steps are easy to purify via simple filtration. The REM linker strategy is attractive because of its recyclability and traceless nature. Once a reaction scheme is completed, the linker can be reused multiple times. In a typical solid-phase synthesis, the product contains either a part of or the whole linker, which can prove undesirable. The REM linker is "traceless" and the point of attachment between the product and the polymer is indistinguishable. The high diastereoselectivity of the intramolecular 1,3-dipolar cycloaddition is well documented. Limited by the insolubility of the solid support, the reaction progression can only be monitored by a change in the functional groups (if any) via infrared (IR) spectroscopy. Thus, the structural identification of intermediates cannot be characterized by conventional nuclear magnetic resonance (NMR) spectroscopy. Other limitations to this method stem from the compatibilities of the polymer/linker to the desired chemical reaction scheme. Herein we report a protocol that allows for the convenient production of spirocyclic heterocycles that, with simple modifications, can be automated with high-throughput techniques.

Introduction

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Despite recent discoveries using highly-functionalized spirocyclic heterocycles in a number of biological systems1, a convenient pathway is still necessary for their easy manufacture. Such systems and uses for these heterocycles include: MDM2 inhibition and other anticancer activities2,3,4,5, enzyme inhibition6,7,8, antibiotic activity9,10, fluorescent tagging10,11,12, enantioselective binding for DNA probes13,14,15 and RNA targeting16, along with numerous potential applications to therapeutics17,18,19. With an increasing demand for these heterocycles, current literature remains divided about which synthetic pathway is best. Modern synthetic approaches to this problem use isatin and isatin derivatives as starting materials for a variety of heterocycles20,21, complicated intramolecular rearrangements22,23,24,25, Lewis acid1,26,27 or transition metal catalysis17,28,29,30, or asymmetric processes31. While these procedures have had success in producing specific spirocyclic oximes with limited functionality, a synthetic strategy for producing a library of molecules with high diastereoselectivity has been explored relatively less32.

The technique presented here shows that these molecules of interest can be generated using a number of well-understood synthetic techniques in tandem. Starting with the synthesis of the molecule on a solid support using a REM linker and intramolecular silyl nitronate-olefin cycloaddition (ISOC), the proposed pathway deploys a nonlinear route, characterized by bond severing in a tricyclic system, leaving a highly functionalized heterocycle. REM linkers, known for their convenience and recyclability, utilize a solid support to synthesize tertiary amines33. Due to the ease of purification accredited to the REM linker via simple filtration, this solid-phase synthesis technique provides scientists with a recyclable and traceless linker, which has been used here. Once the reaction is complete, the REM linker is regenerated and can be reused multiple times. The REM linker is also traceless because, unlike many solid-phase linkers, the point of attachment between the product and the polymer is indistinguishable34,35. Also well-studied and understood is the ISOC reaction, useful in the synthesis of pyrrolidine oximes36,37. Perhaps better known as a 1,3-dipolar cycloaddition, these reactions form a number of heterocycles with high diastereoselectivity38,39,40,41,42,43,44,45. Using the modified REM-coupled-ISOC technique for the synthesis of spirocyclic molecules yields a highly diastereoselective product.Herein, we report on the efficient production of spirocyclic oximes using a new synthetic approach, combining two well-understood pathways and readily available starting materials.

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Protocol

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CAUTION: Please consult all relevant material safety data sheets (MSDS) before use. Several of the chemicals used in these syntheses are acutely toxic and carcinogenic. Please use all appropriate safety practices when performing the following reactions, including the use of engineering controls (fume hood and IR and NMR spectrometers) and personal protective equipment (safety goggles, gloves, lab coat, full-length pants, and closed-toe shoes).

1. Michael Addition of Furfurylamine to the REM Linker

NOTE: The duration of this step is 25 min for the set-up and 24 h of reaction time.

  1. Add 1 g (1 equiv.) of REM resin, 20 mL (20 equiv.) of dimethylformamide (DMF), and 2.4 mL of furfurylamine to a 25 mL solid-phase reaction vessel.
  2. Agitate the reaction vessel for 24 h at room temperature using a shaker following the reaction initiation. The vessel is capped during the reaction.
    NOTE: Ensure that the resin does not sit at the bottom of the vessel and mixes thoroughly.
  3. Drain the solution and wash the resin 1x with 5 mL of DMF after the reaction is complete.
    1. Then, wash the resin 4x, alternating between 5 mL of dichloromethane (DCM) and 5 mL of methanol.
    2. Following the washes, dry the resin thoroughly with compressed air in the reaction vessel for 30 min.
    3. Monitor the reaction progress for a change in IR stretching frequencies, as shown in Table 1.

2. Tandem Michael Addition/1,3-dipolar Cycloaddition

NOTE: The duration of this step is 25 min for the set-up and 48 h of reaction time.

  1. Take the dry resin and add 1.48 mL (5 equiv.) of triethylamine (TEA), 10 mL of dry toluene, and 0.637 g (2 equiv.) of nitro-olefin to the reaction vessel.
  2. Add 1 mL (4 equiv.) of trimethylsilyl chloride (TMSCl) to the reaction vessel in a well-ventilated fume hood.
    CAUTION: This reaction will form HCl gas. Do not cap the reaction vessel until the gas has been released under a fume hood.
  3. Securely cap the reaction vessel and agitate using a shaker for 48 h at room temperature. Ensure that the resin mixes thoroughly with the reagents.
  4. Quench the reaction with 5 mL of methanol.
    1. Drain the solution from the vessel and, then, wash the resin 4x, alternating between 5 mL of DCM and 5 mL of methanol.
    2. Following the washes, dry the resin thoroughly with compressed air in the reaction vessel for 30 min.
    3. Monitor the reaction progress by observing a change in the IR stretching frequencies, as shown in Table 1.

3. Ring Opening of Resin-bound Isoxazole by Tetra-n-butylammonium Fluoride

NOTE: The duration of this step is 10 min for the set-up and 12 h of reaction time.

  1. Place 1 mL of dry tetrahydrofuran (THF) in the reaction vessel with the dry resin. Then, add 1.24 mL (2 equiv.) of 1 M tetra-n-butylammonium fluoride (TBAF) in THF to the reaction vessel.
  2. Using a shaker, agitate the solution for 12 h at room temperature and ensure that the resin thoroughly mixes with the solution.
  3. Drain the solution and wash the resin 1x with 5 mL of THF after the reaction is complete.
    1. Then, wash the resin 4x, alternating between 5 mL of DCM and 5 mL of methanol.
    2. Following the washes, dry the resin thoroughly with compressed air in the reaction vessel for 30 min.
    3. Monitor the reaction progress by observing a change in the IR stretching frequencies, as shown in Table 1.

4. N-alkylation of the Resin-bound Heterocycle to Form Quaternary Amine

NOTE: The duration of this step is 10 min for the set-up and 24 h of reaction time.

  1. Take the dry resin in the reaction vessel and add 5 mL of DMF.
    1. Then, add 1 mL of alkyl halide (10 equiv.) to the vessel and agitate using a shaker for 24 h at room temperature. Ensure the thorough mixing of the resin with the reagents.
  2. Drain the solution and wash the resin 1x with 5 mL of DMF after the reaction is complete.
    1. Then, wash the resin 4x, alternating between 5 mL of DCM and 5 mL of methanol.
    2. Following the washes, dry the resin thoroughly with compressed air in the reaction vessel for 30 min.
    3. Monitor the reaction progress by observing a change in IR stretching frequencies as shown in Table 1.

5. β-elimination of the Quaternary Amine from the Polymer Support

NOTE: The duration of this step is 15 min for the set-up and 24 h of reaction time.

  1. Take the dry resin and add 3 mL of DCM to the reaction vessel.
    1. Then, add 1.5 mL (5 equiv.) of TEA to the reaction vessel to cleave the heterocycle from the polymer support.
    2. Agitate using a shaker for 24 h, ensuring the thorough mixing of the resin with the solution. Drain the solution from the resin.
      NOTE: Do not discard since the cleaved product is in the TEA/DCM solution.
  2. Wash the resin 4x, alternating between 5 mL of DCM and 5 mL of methanol.
    NOTE: Do not discard.
    1. Combine the elution from all washes in steps 5.1.2 and 5.2 and concentrate it via rotatory evaporation.
    2. Purify the spirocyclic oxime by trituration: add 0.5 mL of hot methanol to dissolve any impurities. The pure product will crash out of the solution and is collected via gravity filtration.
  3. Following two washes with 5 mL of DCM for reuse in future experiments, thoroughly dry the resin with compressed air in the reaction vessel for 30 min.
    1. Monitor the reaction progress by observing a change in the IR stretching frequencies, as shown in Table 1.

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Results

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As outlined in the procedure above, the synthetic route to spirocyclic oximes (see Figure 1) begins with the Michael addition of furfurylamine to compound 1, the REM linker, to afford 2. A subsequent Michael addition and 1,3-dipolar cycloaddition of the support 2 using various β-nitrostyrene derivatives yield the tricyclic compound 3, an N-silyloxy isoxazolidine with four unique ster...

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Discussion

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In a typical REM linker/solid-phase synthetic strategy, prior to the release of an amine from the solid support, it is critical to form a quaternary ammonium salt, as described in section 4 of the protocol39. Due to the steric hindrance of the tricyclic system and bulky R2 groups (benzyl and octyl halides), only small alkylating reagents (methyl and allyl halides) could be utilized in this reaction46. With a simple modification, allowing for the addition and use ...

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Disclosures

$$\rightleftharpoonup{xx}$$ $$\longleftharp{xx}$$, $$\longrightharp{xx}$$,

The authors have nothing to disclose.

Acknowledgements

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This work was funded by a grant from the Faculty Research Council to K.S. Huang (Azusa Pacific University - United States). C.R. Drisko is a recipient of the John Stauffer Scholarship and the Gencarella Undergraduate Research Grant. S.A. Griffin received an S2S Undergraduate Research Fellowship from the Department of Biology and Chemistry.

figure-acknowledgements-1

Authors (left to right) Cody Drisko, Dr. Kevin Huang and Silas Griffin conducted the experiments and prepared the manuscript. Cody Drisko is a John Stauffer Fellow and a recipient of the Gencarela Research Grant. Silas is a S2S Azusa Pacific University Research Fellow. Dr. Kevin Huang provided the research mentoring and is a recipient of the Azusa Pacific University Faculty Research Council Grant.

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Materials

List of materials used in this article
NameCompanyCatalog NumberComments
Chemicals
REM ResinNova Biochem8551010005Solid Polymer Support; 1.1 mmol/g loading
FurfurylamineAcros Organics119800050Reagent
Dimethylformamide (DMF)Sigma-Aldrich227056Solvent
Dichloromethane (DCM)Sigma-Aldrich270997Solvent
MethanolSigma-Aldrich34860Solvent
trans-4-bromo-β-nitrostyreneSigma-Aldrich400017Nitro-olefin solid
trans-3,4-dimethoxy-β-nitrostyreneSigma-AldrichS752215Nitro-olefin solid
trans-2,4-dichloro-β-nitrostyreneSigma-Aldrich642169Nitro-olefin solid
trans-β-nitrostyreneSigma-AldrichN26806Nitro-olefin solid
Triethylamine (TEA)Sigma-AldrichT0886Solvent
Trimethylsilyl chloride (TMSCl)Sigma-Aldrich386529Reagent; CAUTION - highly volatile; creates HCl gas
Tetra-n-butylammonium fluoride (TBAF) in Tetrahydrofuran (THF)Sigma-Aldrich216143Reagent
Tetrahydrofuran (THF)Sigma-Aldrich401757Reagent
1-BromooctaneSigma-Aldrich152951Alkyl-halide
IodomethaneSigma-Aldrich289566Alkyl-halide
AllylbromideSigma-Aldrich337528Alkyl-halide
BenzylbromideSigma-AldrichB17905Alkyl-halide
Glassware/Instrumentation
25 mL solid-phase reaction vesselChemglassCG-1861-02Glassware with filter
Thermo Scientific Nicole iS5Thermo ScientificIQLAADGAAGFAHDMAZAInstrument
AVANCE III NMR SpectrometerBrukerN/AInstrument; 300 MHz; Solvents: CDCl3 and CD3OH
Wrist-Action Shaker Model 75Burrell Scientific757950819Instrument

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REM Linker Strategy13 Dipolar CycloadditionIR SpectroscopyResin WashingCompressed Air DryingTriethylamine QuenchTetra n butylammonium FluorideRotary Evaporator

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