Synthesis Golf IX: Tezacaftor

Question

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).

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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:

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

Answer 1

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

(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.

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Fragment 2

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

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Union

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

Answer 2

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: Synthesis of fragments A and B is outlined below:

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.

8. p-Nitroaniline is brominated;

9. Sonogashira coupling;

10. Gold-catalyzed hydroamination;

11. 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);

12. Reduction of the nitro group.

Now comes the endgame:

13. Amide formation;

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

15. Piperidine removes Fmoc;

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

17. 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: 18. Methylacetoacetate is methylated twice;

19. Formation of enol triflate;

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

Total step count: 20

Longest linear sequence: 12

Answer 3

FIRST Fragment

a - acetone dimethyl acetal, zirconium tetrachloride

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

c - paraformaldehyde, TFA

d - TBSCl, imidazole

The combined product:

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

SECOND Fragment

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