Synthesis Golf X: TAK-457
Fragment #1 Preparation



1) An exact preparation of an aryl imidazolidinone (54% Yield)1
2) A modified preparation of a tetrazole from an aniline derivative (90% yield with pure aniline)2
3) A modified acetal formation (protocol modifications based on urea) (no reported yield)3  

Fragment #2 Preparation



1) An exact preparation of an alpha-bromophenone (Hell-Volhard-Zelinski Reaction) (97% yield --likely prior to purification)4
2) Modified coupling of 1,2,4-triazole and alpha-bromophenone (100% yield with chloroacetone -- likely prior to purification)5
3) Wittig reaction modification (73% yield with phenyl methyl ketone)6
4) A modified triazolium formation (82% yield with methyl iodide)7
5) Stereoselective Jacobsen epoxidation (92% yield with 1-phenylcyclohexene)8 

Final Fragment Coupling



1) Deprotonation of the amine with LDA
2) Epoxide ring opening followed by the protonation of the alkoxide and hydrolysis of the acetal to yield the final product

Stereochemical and General Considerations

The use of the Jacobsen epoxide formation allows for the use of the (L, L) Jacobsen catalyst in the final steps of the synthesis to yield the enantiomer of TAK-457. Synthesis of the other stereoisomer would require modification of earlier steps in the reaction. 

Longest Linear Sequence: 5 steps
Total Number of Steps: 9 steps (I consider the final two steps as one since they are performed without subsequent purification)

Comment on 1,2,4-Triazole Ring: Yes, I did not prepare the triazole ring directly; however, this seems to be the more efficient route.

Comment on Wittig Reaction: This is the step I am probably the most worried about. The steric bulk from the phenyl group may be enough to slightly favor the desired enantiomer; however, this cannot be determined until further experimentation is performed.

References


Stabile, P.; Lamonica, A.; Ribecai, A.; Castoldi, D.; Guercio, G.; Curcuruto, O. Mild, Convenient and Versatile Cu-mediated synthesis of N-Aryl-2-imidazolidinones. Tetrahedron Lett. (2010) 51 (24). 3232–3235. DOI:10.1016/j.tetlet.2010.04.064
Kundu, D.; Majee, A.; Hajra, A. Indium Triflate-Catalyzed One-Pot Synthesis of 1-Substituted-1H-1,2,3,4-Tetrazoles Under Solvent-Free Conditions. Tetrahedron Lett. (2009) 50 (22). 2668–2670. DOI:10.1016/j.tetlet.2009.03.131 
Shuai, F.; Wang, X.; Zhang, J. Preparation of Dipyridamole Active Pharmaceutical Ingredient. CNIPA Patent 108069972, Nov 16, 2016
Alonso-Alija, Cristina; et al. Preparation of Amino(monocyclic aroyl)pyridinones that Inhibit p38 Map Kinase for use as Antiinflammatory Agents. WIPO Patent 2003076405, Sep. 18, 2003
Sun, Y.; Huang, N.-Y.; Ding, M.-W. Efficient Synthesis of 6-(1H-1,2,4-Triazol-1-yl)-thieno[2,3-d]pyrimidin-4(3H)-ones via an Iminophosphorane. Synth. Commun. (2010) 40 (13). 1985–1991. DOI: 10.1080/00397910903219351 
Pratsch, G.; Overman, L. E. Synthesis of 2,5-Diaryl-1,5-dienes from Allylic Bromides Using Visible-Light Photoredox Catalysis. J. Org. Chem. (2015) 80 (22). 11388–11397. DOI:10.1021/acs.joc.5b01962
Myles, L.; Gathergood, N.; Connon, S. J. The Catalytic Versatility of Low Toxicity Dialkyltriazolium Salts: in Situ Modification Facilitates Diametrically Opposed Catalysis Modes in One Pot. Chem. Commun. (2013) 49 (46). 5316. DOI:10.1039/c3cc41588k 
Brandes, B. D.; Jacobsen, E. N. Highly Enantioselective, Catalytic Epoxidation of Trisubstituted Olefins. J. Org. Chem. (1994) 59 (16). 4378–4380. DOI:10.1021/jo00095a009