Synthesis of thiohydantoins

A one-pot synthesis of thiohydantoins has been developed using microwave heating [72]. A small subset of p-substituted benzaldehydes, prepared in situ from p-bromobenzaldehyde by microwave-assisted Suzuki or Negishi reactions, was reacted in one pot by reductive amination followed by cyclization with a thioisocyanate catalyzed by polystyrene-bound dimethyl-aminopyridine (PS-DMAP) or triethylamine, all carried out under microwave irradiation, to give the thiohydantoin products in up to 68% isolated yield (Scheme 16). 

In a separate study, Ohberg and Westman applied the same PS-DMAP in a one-pot microwave-induced base-catalyzed reaction of N-aryl and N-alkyl amino acids (or esters) and thioisocyanates for the library synthesis of thiohydantoins (Scheme 7.115) [136]. Thiohydantoins are of interest due to their ease of preparation and the range of biological properties associated with this heterocyclic ring system. The use of PS-DMAP as the base in this reaction gave slightly lower yields compared to when triethylamine (TEA) was used, but it resulted in a cleaner reaction mixture and an easier purification procedure. Cyclizations of a number of N-substituted... 

Microwave-induced imine formation, subsequent reduction with NaBH(OAc)3 and cyclisation of the resulting amino acid with isothiocyanates was used in an efficient one-pot multi-step synthesis of thiohydantoins (Scheme 4.26). The reductive animation was conducted as a two-step procedure to avoid direct reduction of the aldehyde at high temperatures48. 

The inability of C-terminal proline to be derivatized to a thiohydantoin has been a major impediment to the development of a routine method for the C-terminal sequence analysis of proteins and peptides. Since the method was first described in 1926 (2), the derivatization of C-terminal proline has been problematic. While over the years a few investigators have reported the derivatization of proline, either with the free amino acid or on a peptide, to a thiohydantoin (6-8), others have been unable to obtain any experimental evidence for the formation of a thiohydantoin derivative of proline (9-12). Recently, utilizing a procedure similar to that described by Kubo et al. (6), Inglis et al. (13) have described the successful synthesis of thiohydantoin proline from N-acetylproline. This was done by the one-step reaction of acetic anhydride, acetic acid, trifluoroacetic acid, and ammonium thiocyanate with N-acetyl proline. We have reproduced this synthesis and further developed it to a large scale synthesis of TH-Proline. 

We have described a simple procedure for the large scale (200 mg) synthesis of thiohydantoin proline from N-acet proline and extensively characterized this analogue. The thiohydantoin derivative of proline is conveniently obtained as a white powder which is stable to long term storage. The availability of a thiohydantoin proline standard is critical for the evaluation of automated sequencing results. 

An efficient one-pot protocol has been developed for the solution-phase synthesis of thiohydantoins (Scheme 4) [10]. After reductive alkylation of amino acid esters 16, the isothiocyanate was added together with triethylamine, leading to thiohydantoin products 18. The work-up procedure was performed by adding gly-... 

As shown above (Scheme 4), this strategy has been employed for the synthesis of thiohydantoins 18, as well as for the synthesis of amides and ureas 45 (Scheme 15) [10, 44]. Glycine and potassium sarcosinate were chosen as the quenching agents for their bifunctional nature. The amine end of the amino acid quenches the excess electrophile and the carboxylic acid functionality renders the amino acid bound impurity soluble in aqueous media. 

Figure 2 Synthesis of thiohydantoin library. Nine amino acids (Gly, Ala, Val, Phe, Asp, Ser, Met, Trp, His), 18 aromatic aldehydes (9 subst. Ph, 2 subst. Py, 4 five-member heterocyclic, bicyclic), and 19 isothiocyanates (12 aromatic, 1 bicyclic, 3 aliphatic, 3 sat. cyclic).

Cyclization to the desired head-to-taU-linked bis-benzimidazoles can also be performed by reaction of aryl or alkyl isothiocyanates with N,N -dicyclohexylcarbodi-imide (DCC) [83]. In a closely related and more recent study by the same group, mercury chloride was used as a catalyst to perform cyclization to the benzimidazoles [84]. Another application of the bis-hydroxylated polymer support PEG 6000, microwave-accelerated liquid-phase synthesis of thiohydantoins, has been reported [85, 86]. 

The microwave-assisted one-pot three-step synthesis of thiohydantoins has been studied together with a polymer-supported catalyst and/or reagent [55]. Cyclization of a number of AT-substituted amino acids of type 50 and thioiso-cyanates 51 has given satisfactory yields within 5 min at 170 to 180 °C (see Scheme 29). Polymer-supported dimethylaminopyridine (PS-DMAP) 52 has been utilized as a supported base herein to catalyse the reaction however, in most cases the yield was comparatively lower to the use of triethylamine (TEA). PS-DMAP also assisted in simplifying the purification. 

C. Gasch, B. A. B. Salameh, M. A. Pradera, and J. Fuentes, Isothiocyanatoulosonates, a new type of glycosyl isothiocyanate useful for the sterocontrolled synthesis of thiohydantoin spironucleosides, Tetrahedron Lett., 42 (2001) 8615-8617. 

Application of effective parallel purification methods continues to improve the quality of products prepared using solution phase approaches. Sim and Ganesan [14] developed a one-pot three component synthesis of thiohydantoins using the reductive am-... 

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