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I shall try to revive this!
A full FAQ post has been written on chemistry.meta.SE, explaining the premise of synthesis golf and the 'rules'. Please take a look at this before answering (if you haven't already).

TAK-457 is a drug (more accurately, an injectable prodrug of TAK-456) that displays antifungal activity:[1,2,3]

Structure of TAK-457

Some rules, as usual:

  • At most one chiral centre may be bought in your starting material(s). [Chiral catalysts, ligands, auxiliaries, etc. do not fall under this rule.]

  • Your synthesis must feature a method for construction of either the triazole or tetrazole ring (i.e. do not buy both).

  • The counterion doesn't matter.

  • Bonus points for synthesis that can be adapted to produce the other three stereoisomers of the drug (preferably via late stage diversification as opposed to, say, using a different enantiomer of starting material). These stereoisomers were of interest.[4]

References

  1. Ichikawa, T.; Kitazaki, T.; Matsushita, Y.; Yamada, M.; Hayashi, R.; Yamaguchi, M.; Kiyota, Y.; Okonogi, K.; Itoh, K. Optically Active Antifungal Azoles. XII. Synthesis and Antifungal Activity of the Water-Soluble Prodrugs of 1-[(1​R,2​R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1​H-1,2,4-triazol-1-yl)propyl]-3-[4-(1​H-1-tetrazolyl)phenyl]-2-imidazolidinone. Chem. Pharm. Bull. 2001, 49 (9), 1102–1109. DOI: 10.1248/cpb.49.1102.

  2. Hayashi, R.; Kitamoto, N.; Iizawa, Y.; Ichikawa, T.; Itoh, K.; Kitazaki, T.; Okonogi, K. Efficacy of TAK-457, a novel intravenous triazole, against invasive pulmonary aspergillosis in neutropenic mice. Antimicrob. Agents Chemother. 2002, 46 (2), 283–287. DOI: 10.1128/AAC.46.2.283-287.2002.

  3. Tsuchimori, N.; Hayashi, R.; Kitamoto, N.; Asai, K.; Kitazaki, T.; Iizawa, Y.; Itoh, K.; Okonogi, K. In Vitro and In Vivo Antifungal Activities of TAK-456, a Novel Oral Triazole with a Broad Antifungal Spectrum. Antimicrob. Agents Chemother. 2002, 46 (5), 1388-1393. DOI: 10.1128/AAC.46.5.1388-1393.2002.

  4. Ichikawa, T.; Yamada, M.; Yamaguchi, M.; Kitazaki, T.; Matsushita, Y.; Higashikawa, K.; Itoh, K. Optically Active Antifungal Azoles. XIII. Synthesis of Stereoisomers and Metabolites of 1-[(1​R,2​R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1​H-1,2,4-triazol-1-yl)propyl]-3-[4-(1​H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456). Chem. Pharm. Bull. 2001, 49 (9), 1110–1119. DOI: 10.1248/cpb.49.1110.

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    $\begingroup$ Those heterocycles are harder than they look... :/ $\endgroup$
    – Zhe
    Nov 6, 2018 at 20:31
  • $\begingroup$ Adopting this synthesis for late-stage diversification was definitely a challenge, but the Jacobsen epoxidation fit the problem perfectly! I am actually surprised the Jacobsen epoxidation is not taught more in organic chemistry. It is much more versatile than the Sharp Asymmetric Epoxidation. $\endgroup$
    – Eli Jones
    May 13, 2020 at 17:43
  • $\begingroup$ @orthocresol♦: I will have to admit, this synthesis was probably the most fun I have had in the last month! Will you be posting more synthesis-golf questions in the future? I enjoy seeing the various approaches to total synthesis people come up with! $\endgroup$
    – Eli Jones
    May 14, 2020 at 0:20
  • $\begingroup$ @EliJones thanks, I am glad you liked it. In principle I am not opposed to it. In practice I don't have all that much time (and truthfully there hasn't been that much interest in recent years). You're more than welcome to copy the format. $\endgroup$
    – orthocresol
    May 14, 2020 at 4:53

2 Answers 2

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Fragment #1 Preparation

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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

Fragment #2

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

Final 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

  1. 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
  2. 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
  3. Shuai, F.; Wang, X.; Zhang, J. Preparation of Dipyridamole Active Pharmaceutical Ingredient. CNIPA Patent 108069972, Nov 16, 2016
  4. 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
  5. 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
  6. 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
  7. 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 
  8. 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
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    $\begingroup$ Wouldn't protecting carbonyl also break tetrazole? $\endgroup$
    – Mithoron
    May 17, 2020 at 21:02
  • $\begingroup$ The protecting step is not necessary for protecting the carbonyl from reacting as much as it is for activating the amide nitrogen. If I tried deprotonating the amide, it would just result in the formation of an alpha-amino alkoxide when I treat it with LDA. It would be difficult to avoid this acetal formation and the tetrazole ring from interfering. I have not necessarily seen any literature claiming catalytic p-TSA would break the tetrazole, but I suppose this is something that would need to be determined experimentally! $\endgroup$
    – Eli Jones
    May 18, 2020 at 0:40
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    $\begingroup$ Hmm, prophylactically it probably could be done before forming tetrazole. Let's call it a hunch but this unstable ring might be best made in the end, just to be sure ;) $\endgroup$
    – Mithoron
    May 18, 2020 at 0:54
  • $\begingroup$ Thanks for the advice! I thought about forming it before making the tetrazole; however, I think that would render the NH too active. This might then result in a mixture of products when I try to form the tetrazole from aniline. It might be best to form the tetrazole at the end, but my synthesis would be less suitable for late-stage diversification (for multiple stereoisomers). $\endgroup$
    – Eli Jones
    May 18, 2020 at 1:15
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    $\begingroup$ If your Wittig isn't selective enough, that's an easy way to access two diastereomers at once. *taps forehead* $\endgroup$
    – orthocresol
    May 18, 2020 at 16:26
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Body must be at least 30 characters.

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    $\begingroup$ "Body must be at least 30 characters." Yes, and shoes should be tied. Please clean up your answer, as it stands it's not suitable for prime-time. $\endgroup$
    – Todd Minehardt
    Dec 20, 2019 at 0:56
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    $\begingroup$ @ToddMinehardt I am sorry the answer is not typed up. I have not had time to type it up and since I left university this year, I do not have access to ChemDraw. Please let me know if any of the reactions are not clear and I will try to elaborate. $\endgroup$
    – Laksh
    Dec 25, 2019 at 16:06

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