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SYNTHESIS OF FUNCTIONALIZED CYCLOBUTANES AS A CONFORMATIONAL RESTRICTION TOOL FOR THE MEDICINAL CHEMISTRY
Prof. Dmitriy M. Volochnyuk 257th ACS National Meeting April 2019 Orlando
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Small cycles as tools for drug discovery
Fang Z et al Future Med. Chem. 2014, 6, 885-901., M. L. Wrobleski et al Bioorg. Med. Chem. Lett. 2006, 16, 3859-3863., S. P. Runyon J. Org. Chem. 2016, 10.1021/acs.joc.6b01366.
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Small cycles as tools for drug discovery
Z. Rappoport, J.F. Liebman “The chemistry of cyclobutanes” John Wiley & Sons Ltd, 2005. D. Bonivento et al. J.Biol.Chem., 2010, 285, 36849-36856
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Cyclopropanes vs Cyclobutanes
Cyclopropanes Conformationally restricted Easy accessible Easy controlled
stereochemistry Many PoC in medicinal
chemistry Metabolically unstable
Cyclopropanes Conformationally restricted Hardly accessible ([2+2]
photochemistry, kinetically disfavored cyclizations, etc)
Hardly controlled stereochemistry
Limited PoC in medicinal chemistry
Metabolically stable More stereo variable
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Agenda
1. Design and synthesis of cyclobutane-derived fluorinated analogues of polar amino acids (such as lysine and serine analogues) which can be used as 19F NMR labels. 2. Cyclobutane-derived scaffolds (such as spiro[3.3]heptane) in design of building blocks for medicinal chemistry.
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Known (before us) 19F NMR labels
Low reaction ability in solid-phase synthesis
Easy racemization
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[1.1.1]-Propellane story
racemization ideal 19F-NMR label Dr. P. Mykhailiuk
2006:
Mikhailiuk, P. K Angew. Chem. IE 2006, 45, 5659-5661. doi:10.1002/anie.200600346.
2010:
0.48 mol of [1.1.1]-propellane was used leading to 64 g of CF3-Bpg from 1 run
J. Fluor. Chem. 2010, 131, 217–220. doi:10.1016/j.jfluchem.2009.10.004.
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Known 19F NMR labels
Arg Lys
Asp Glu
His Asn Gln
Ser Thr
Pro
Gly
Cys
Tyr
Ala Met
Trp
Phe
Leu
Val Ile -5
-4
-3
-2
-1
0
1
2
3
4
5
0 2 4 6 8 10
Hyd
rop
hil
isty
Size
! Today’s talk
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Design of CF3-CBSer, TCBLys, TCBArg
• All achiral • CF3-CBSer synthesized and validated by incorporation into Temporin A • TCBLys (both isomers) synthesized Validated by incorporation into PGLa(Nle) • TCBArg only synthesized, not published results
Tkachenko, A. N. et al. Angew. Chem. Int. Ed. 2013, 52, 1486-1489 Michurin, O. M. et al. Angew. Chem. Int. Ed. 2016, 55, 14595–14599
Prof Igor Komarov
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Synthesis of CF3-CbSer
X-Ray
Tkachenko, A. N. et al. Angew. Chem. Int. Ed. 2013, 52, 1486-1489
Synlett 2009, p. 1827
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Temporin А: FLPLIGRVLSGIL-NH2
Prof. S. Afonin Prof. A. Ulrich
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Synthesis of TCBLys
• 13 g of 16 from 1 synthetic run
Michurin, O. M. et al. Angew. Chem. Int. Ed. 2016, 55, 14595–14599
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Synthesis of TCBLys
Michurin, O. M. et al. Angew. Chem. Int. Ed. 2016, 55, 14595–14599
X-Ray
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PGLa(Nle) Mutants
PGla(Nle) G(Nle)ASKAGAIAGKIAKVALKAL-NH2
Z-19 G(Nle)ASKAGAIAGKIAKVAL(cis-TCBLys)AL-NH2
E-19 G(Nle)ASKAGAIAGKIAKVAL(trans-TCBLys)AL-NH2
Z-15 G(Nle)ASKAGAIAGKIA(cis-TCBLys)VALKAL-NH2
E-15 G(Nle)ASKAGAIAGKIA(trans-TCBLys)VALKAL-NH2
Z-12 G(Nle)ASKAGAIAG(cis-TCBLys)IAKVALKAL-NH2
E-12 G(Nle)ASKAGAIAG(trans-TCBLys)IAKVALKAL-NH2
Michurin, O. M. et al. Angew. Chem. Int. Ed. 2016, 55, 14595–14599
Prof. S. Afonin Prof. A. Ulrich
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PGLa(Nle) Mutants
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CF3-CBSer, TCBLys
• First cationic CF3 label for solid-state 19F NMR studies
• pKa(-NH2) = 9.3 and 9.7 (close to that of Lys) • Validated by incorporation into PGLa(Nle) • Allowed to considerably increase the precision of the
peptide orientational analysis in model membranes
• First polar CF3 label for solid-state 19F NMR studies
• pKa(OH) = 11.7 (close to that of Ser/Thr)
• Validated by incorporation into Temporin A
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2. Cyclobutane-derived scaffolds (such as spiro[3.3]heptane) in design of building blocks for medicinal chemistry.
The world’s largest stock 170,000 Building blocks in stock 50% of the world’s stock +2,000 new building blocks each month In-house synthesis Original Enamine scientific design
Enamine # 1 in Building Blocks
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Radchenko, D. et al. J. Org. Chem. 2010, 75, 5941-5952 Yarmolchuk, V. S. et al. J. Org. Chem. 2011, 76, 7010-7016 Grygorenko O. O. et al. Mol. Div. 2012, 477–487
Dr. O. Grygorenko
Exit Vector Plot (EVP)
= 0 1 = 0 2 = 0
= 0/180 1 = 24 2 = 25
= 9/84 1 = 44/92 2 = 26/40
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7 steps, 19% overall
yield
9 steps, 7% overall
yield
Cyclobutane-derived diamines
Radchenko, D. et al. J. Org. Chem. 2010, 75, 5941-5952
Dr. D. Radchenko
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9 steps, 15% overall
yield
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2,6-Spiro[3.3]heptane diamines
Radchenko, D. et al. J. Org. Chem. 2010, 75, 5941-5952
Dr. D. Radchenko
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Azaspiro[3.3]heptane diamines
Radchenko, D. et al. J. Org. Chem. 2010, 75, 5941-5952
11 steps, 18% overall
yield
Dr. D. Radchenko
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Cyclobutane-derived diamines
Mityuk, A. P. et al. Org. Lett. 2010, 12, 4372–4375
Mityuk, A. P.; Denisenko A. V. et al. Tetrahedron Lett. 2010, 51, 1790–1792 Mityuk, A. P.; Denisenko A. V. et al. Synthesis 2010, 493–497
Alex Denisenko
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X-ray study
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Radchenko, D. et al. J. Org. Chem. 2010, 75, 5941-5952 Mityuk, A. P. et al. Org. Lett. 2010, 12, 4372–4375
r = 2.84 Å = 178 1 = 22 2 = 27
r = 4.26 Å = 1 1 = 41 2 = 25
CCDC database
data
1+2 = 49 1+2 = 66
r = 4.48 Å = 179 1 = 33 2 = 10
1+2 = 43
r = 4.58 Å = 2 1 = 31 2 = 31
1+2 = 61
r = 2.73 Å = 0 1 = 79 2 = 71
1+2 = 150 (30 )
r = 6.81 Å = 113 1 = 23 2 = 12
! r = 5.49 Å = 131 1 = 6 2 = 18
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X-ray study / EVP analysis
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1,6-Spiro[3.3]heptane diamines
411 compounds (154 described in 37 papers)
34 patents 1-st examples: Chem. Ber. 1907, 40, 3888
“Fecht diacid”
Unknown
Unknown
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6 6
1 1
1 1 1 1 5 5
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1,6- vs 2,6-Spiro[3.3]heptanes
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X-Ray
A. V. Chernykh, D. M. Volochnyuk et al ., RSC Advances 2014, 4, 10894-10902.
Key intermediates
Dr. A. Chernykh
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A. V. Chernykh, D. M. Volochnyuk et al ., RSC Advances 2014, 4, 10894-10902.
Key intermediates
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11 steps, 2.89%
D. S. Radchenko, D. M. Volochnyuk et al ., J. Org. Chem., 2015, 80, 3974-3981.
1,6-Spiro[3.3]heptane diamines
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D. S. Radchenko, D. M. Volochnyuk et al ., J. Org. Chem., 2015, 80, 3974-3981.
X-ray study
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Compound r, Ǻ
1, 2,
26a 3.59 77 46
26b 3.59 76 46
27 2.95 68 27
26c 3.44 81 30
26d 3.41 81 30
28 2.53 81 35
D. S. Radchenko, D. M. Volochnyuk et al ., J. Org. Chem., 2015, 80, 3974-3981.
X-ray study / EVP analysis
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O. O. Grygorenko, D. M. Volochnyuk et al ., RSC Advances, 2016, 6, 17595-17605.
X-ray study / EVP analysis
16a,b
17a,b 17c,d
15a 15b
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Acknowledgements
Prof. Igor V. Komarov Prof. Sergii Afonin Prof. Anne Ulrich Dr. Pavel K. Mykhailiuk Dr. Oleksandr O. Grygorenko Dr. Dmitriy S. Radchenko Dr. Anton V. Chernykh
Dr. Anton Tkachenko Oleg Michurin Andrey Mityk Alex Denisenko
THANK YOU FOR YOUR KIND ATTENTION