Solid Phase Organic Synthesis (SPOS)

Soon after application of solid phase synthesis to peptides and nucleotides, the procedure was extended to synthesis of ‘small organic molecules’. This description ‘small compounds’ refers to the large groups of organic molecules that are of interest in drug chemistry (other than peptide and nucleotides) that could serve as drug candidates. Let us briefly look into SPOS.

Elisman’s solid phase synthesis of benzodiazepines (1992) was a landmark paper that drew attention of organic chemists to the power of solid phase synthesis. A combinatorial library of 192 anologues was synthesized, using the following protocol (Fig 6.1).

Fig 6.1: Elisman’s solid phase synthesis of benzodiazepines (1992).

The technique of synthesizing small quantities of small molecules on solid phase methodology could be seen in Denis S. Ermolat’ev’s synthesis of primary amides of N-(pyrimidin-2-yl)amino acids shown below. Note that this protocol

  Denis S. Ermolat’ev et.al., ARKIVOC 2005 (iv) 172-178 

eliminated the need for elaborate purification at every step of the synthesis. The final products obtained after cleavage of resin were reasonably pure for direct spectral identifications (Fig 6.2.)

Fig 6.2 Denis S. Ermolat’ev’s synthesis of primary amides (2005)

Fmoc- protected Wang resin was deprotected and condensed with different N-protected amino acids. Deprotection, condensation with α-Fluoropyrimidine and cleavage gave various primary amides of N-(pyrimidin-2-yl)amino acids. in moderate to good yields. The advantage of solid phase methodology is the short duration needed for the syntheses. The procedure could be applied to linear syntheses as seen above or multi-component condensation reactions (MCC) like Ugi or Biginelli reactions. The methodology has been used in combinatorial synthesis of libraries as well. The following examples illustrate this chemistry. The three-component Biginelli condensation (MCC reaction) was put through SPOS by Doris Dallinger et.al.. The Biginelli condensation

  Doris Dallinger et.al. Pure Appl. Chem., Vol. 76, No. 5, pp. 1017–1024, 2004. 

  P. Biginelli. Gazz. Chim. Ital. 23, 360–413 (1893); also see C. O. Kappe. Tetrahedron 49, 6937–6963 (1993).  

reaction was first reported in 1893. The reaction has found extensive applications in solution phase and solid phase combinatorial chemistry (Fig 6.3).

Fig 6.3: Biginelli synthesis in SPOS

A multi-directional resin cleavage strategy provided greater diversity of products, thereby enhancing the scope of developing larger libraries (Fig 6.4).

Fig 6.4 Solid-phase synthesis of DHPM derivatives based on multidirectional resin cleavage.

J, Li et.al., synthesized a 1,5-substituted 2-(N-alkylamino)-imidazolidin-4-ones library in moderate yield. The resin was removed by acid catalized cleavage (Fig 6.5).

   J. Li et,al., Tetrahedron Letters 1267 (2004) 

Fig 6.5 J.Li’s synthesis of imidazolidinones by SPOS.

Solid phase reagents

Let us look at two other ways of using solid phase chemistry in the creation of libraries. If one attempts to prepare ‘libraries’ directly in solution phase using known solution chemistry, the problem would be the purification of the product library from unused reagents and impurities generated by reagents. The problem has been addressed using ‘capture’ techniques. This could be done in two ways.

1. After the reaction scheme is completed, the required product(s) could be captured on a resin, purified by repeated washing, and finally cleaved to give a purified library.
2. After the reaction scheme is completed, the excess reagents could be scavenged using ‘solid phase scavengers’.

Let us look at a few reactions to illustrate these techniques. The Ugi reaction is a four-component condensation reaction that yields dipeptides through one-pot condensation reaction. This MCC reaction is eminently suited for creating combinatorial libraries in solution as shown in the following example, where the products of interest are captured on a resin (Fig 6.6).

Fig 6.6 Solution phase libraries using Ugi synthesis and solid phase capture technique

The second approach would be to scavenge the excess reagents using solid phase scavengers and leave a ‘clean’ library in solution phase. Kaldor et.al.,

   Kaldor SW, Fritz JE, Tang J, McKinney ER. Discovery of antirhinoviral leads by screening a combinatorial 
   library of ureas prepared using covalent scavengers. Bioorg Med Chem Lett; 6, 3041–3044. (1996)

used this approach in the discovery of antirhinoviral lead compounds. A library of 4000 ureas was prepared as 400 pools of 10 compounds each (Fig 6.7). The libraries were screened. The screened data revealed two compounds, which were individually synthesized and matched.

Fig 6.7 Urea library using scavenger reagents.

A large number of reagents are now available as solid phase reagents to enable functional group transformations without the bother of removing the byproducts arising from the reagent. Some examples are given below (Fig 6.8).

Fig 6.8 Some examples of solid phase scavengers

It is possible to use more than one solid phase reagent in one pot and carry out a series of transformations without the need for isolation of the intermediates (Fig 6.9).

Fig 6.9 Multi-step operations in one pot using solid supported reagents

The methodology has been extended to multi-step sequences. In these cases,

   Parlow JJ, Flynn DL et.al.,. Tetrahedron 1998;54: 4013–4031; Habermann J et.al., . J Chem Soc Perkin 1 1998;3127–3130.

purification of the intermediates and final products were achieved by filtration / washing protocol. The following two examples illustrate the utility of solid phase reagents (Fig 6.10).

Fig 6.10 Multi-step sequences using solid phase reagemts.

Whereever reagents leave a difficult-to-clean byproduct solid phase reagents are most useful. Thus, Wittig reagents and Pd, Pt or Ru complexes find welcome application in SPOS.

Conclusion

Syntheses of peptides and proteins in laboratory marked several major breakthroughs in synthetic methodologies. Solid phase peptide synthesis was a major breakthrough that allowed automation of synthetic protocols. Combinatorial synthesis and screening procedures has drastically reduced the time and cost of ‘Discovery’. These procedures have crossed the boundaries of chemistry and medicine. They are now actively engaged in the discovery of catalysts, process optimizations and discovery of new materials.

References

1. Combinatorial Chemistry By Nicholas K. Terrett, Oxford University Press (1998)
2. Acc. Chem. Res., 29 (3) is devoted to Combinatorial Chemistry
3. Leznoff, C.C. et.al., Account. Chem. Res., 11, 327-333 (1978)
4. DH Drewry, DM Coe, S. Poon, Med. Res. Rev. 19, 97-148(1999).