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

!

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

2 6

6 6

1 1

1 1 1 1 5 5

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