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


The target of this Easter special round of synthesis golf is tezacaptor, which has recently been approved by the FDA as a treatment for cystic fibrosis in combination with ivacaftor:

enter image description here

InChI=1S/C26H28F2N2O6/c1-24(2,14-32)22-10-15-9-17(4-5-19(15)30(22)12-18(33)13-31)29-23(34)25(7-8-25)16-3-6-20-21(11-16)36-26(27,28)35-20/h3-6,9-11,18,31-33H,7-8,12-14H2,1-2H3,(H,29,34)/t18-/m1/s1

  • Any commercial starting material is acceptable (as previously, commercial meaning you can buy it from Sigma-Aldrich) providing it has 10 or fewer carbons
  • The synthesis must include a cyclopropanation (i.e. the starting materials cannot contain a cyclopropane)
  • The synthesis should ideally provide a single stereoisomer of the hydroxyl stereo centre, but to keep things more accessible, a racemic synthesis won't be criticised
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I was trying to come up with something more elegant, but ended up using fairly classical chemistry, which (imo) doesn't need all that much explanation; 13 steps, 9 in longest linear sequence.

Fragment 1

fragment 1

(a) BBr3
(b) CDI
(c) PCl5 forms the geminal dichloride
(d) Et3N•3HF replaces Cl with F [ref J. Fluorine Chem. 2014, 160, 72]
(e) LiHMDS, 1,2-dibromoethane
(f) nitrile to amide, probably acidic conditions – not sure how sensitive this cyclopropane is.


Fragment 2

fragment 2

(g) (CH2O)n, TFA
(h) TBSCl, imidazole
(i) 4-Chlorophenylhydrazine
(j) K2CO3, allyl bromide


Union

union

(k) Pd2(dba)3, Me4t-BuXPhos, K3PO4 [ref J. Am. Chem. Soc. 2007, 129, 13001]
(l) AD-mix-β
(m) TBAF

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    $\begingroup$ I like it. I'm only worried that in step f) the acetal would hydrolyse before the amide in acidic conditions. Maybe the usage of Parkins catalyst could circumvent this issue, but still it's problematic: mdpi.com/2076-3417/5/3/380/htm $\endgroup$ – EJC Mar 30 '18 at 16:26
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    $\begingroup$ BF3 acetic acid complex might be a good choice for hydrolysing the nitrile to the amide $\endgroup$ – Waylander Mar 30 '18 at 18:25
  • $\begingroup$ How to avoid acid in step f. Alkaline peroxide in the presence of a nitrile is an epoxidizing reagent with the by-product an amide. What is the stability of the geminal fluorine moiety in base? $\endgroup$ – user55119 Mar 30 '18 at 21:07
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I am really glad that you are reviving these challenge questions NotEvans. As for the synthesis, the amide disconnection leading to fragments A and B seems like the most simplifying first disconnection: enter image description here Synthesis of fragments A and B is outlined below: enter image description here

  1. Esterification of the readily available acid with isopropyl alcohol under Yamaguchi conditions;
  2. Demethylation (this is why I've chosen to make the isopropyl ester, it shouldn't be destroyed with $\ce{BBr3}$);
  3. Formation of a thiocarbonate crucial for the introduction of two fluorine atoms;
  4. JACS 2010, 132(51), 18199;
  5. Aldol condensation of the ester with formaldehyde;
  6. Ester hydrolysis;
  7. Conversion of the acid to acyl chloride.

enter image description here

  1. p-Nitroaniline is brominated;

  2. Sonogashira coupling;

  3. Gold-catalyzed hydroamination;

  4. Fmoc protection of the indole nitrogen turned out to be necessary at this point (so it doesn't interfere with the coupling with fragment A);

  5. Reduction of the nitro group.

Now comes the endgame:

enter image description here

  1. Amide formation;

  2. Corey-Chaykovsky reaction of a stabilized sulfure ylide is selective for enone-like systems;

  3. Piperidine removes Fmoc;

  4. The indole nitrogen attacks glycidol thus opening the epoxide on the more accessible site;

  5. Reduction of the ester with $\ce{LiBH4}$ should be selective. Several equivalents are needed because of the free hydroxyl groups. My only concern is the stability of the cyclopropane, but other hydride donors could be tried.

EDIT: Here is the synthesis of the alkynyl ester needed to make fragment B: enter image description here 18. Methylacetoacetate is methylated twice;

  1. Formation of enol triflate;

  2. Base-induced elimination of the triflate gives the ester.

Total step count: 20

Longest linear sequence: 12

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    $\begingroup$ The alkyne you are using in the Sonogashira is really expensive - you'd probably choose to make it. Otherwise I'm a huge fan of the gold $\endgroup$ – orthocresol Mar 30 '18 at 1:46
  • $\begingroup$ Yeah, its preparation should be rather simple. I will add it later. $\endgroup$ – EJC Mar 30 '18 at 15:44
  • $\begingroup$ Now that I think about it, the stability of the gem-difluoride with LiBH4 is questionable. $\endgroup$ – EJC Mar 31 '18 at 12:57
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FIRST Fragment

Part 1 Synthesis

a - acetone dimethyl acetal, zirconium tetrachloride

b - 2-Chloro-p-phenylenediamine, cobalt-based catalysis

Part 2 Synthesis

c - paraformaldehyde, TFA

d - TBSCl, imidazole

The combined product:

Part 3 Synthesis

Conditions: Pd(tBu3P)2, potassium phosphate, magnesium sulfate, AcOH, DMA

SECOND Fragment

Synthesis Part 4

e) Carbonyl fluoride, H+

f) paraformaldehyde, TFA

g) Me3S, NaH

Union to Product

h) Both fragments, DCC, catalyst

i) Deprotect

Overall: 10 steps

Longest linear sequence: 5 steps

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  • $\begingroup$ The carbonyl fluoride step is stretching it. It will probably have to be done in a few (3) steps - similar to how orthocresol or Marko did their syntheses, making the total step count 12 and longest liner sequence 7. $\endgroup$ – AS_1000 Apr 8 '18 at 2:45
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    $\begingroup$ In step b, you have two amino groups and you want one to react with the chloride, I don't think that you will be able to achieve the selectivity you desire. $\endgroup$ – EJC Apr 8 '18 at 10:42

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