10.1002/cmdc.201700082
ChemMedChem
FULL PAPER
7.57 (d, J = 8.4 Hz, 1H), 7.45 – 7.39 (m, 2H), 7.33 (t, J = 7.5 Hz, 2H),
4.40 – 4.24 (m, 2H), 4.24 – 4.18 (m, 1H), 3.96 – 3.89 (m, 1H), 2.43 –
2.38 (m, 1H), 1.88 – 1.71 (m, 2H), 1.69 – 1.57 (m, 6H); 13C NMR (151
MHz, DMSO-d6): δ = 173.80, 155.76, 143.85, 143.67, 140.68, 127.56,
126.98, 125.18, 120.05, 65.34, 52.35, 50.33, 46.69, 43.22, 33.09, 27.06;
HRMS (ESI) calcd for C23H22NO4 [M-H]-: m/z = 376.15543, found: m/z =
376.15585.
Crude 15b (20 mg, 0.12 mmol) was mixed with pH 7.0 phosphate buffer
(2 mL), NaHCO3 (16 mg, 0.19 mmol), THF (2 mL) and FmocOSu (39 mg,
0.12 mmol). The reaction mixture was stirred at RT for 20 h, then
concentrated under vacuum. The residue was stirred with 1N aq. HCl
(1mL) for 30 min at RT, then extracted with CH2Cl2 (2 x 20 mL). The
combined organic phases were dried over anhyd Na2SO4, filtered and
concentrated at 30°C to yield 20 mg of turbid oil. Purification by flash
chromatography on 4 g silica gel (MeOH/EtOAc 1:9 to 3:7) gave the title
compound as colorless crystals (12 mg, 27%) with a purity of >90% (1H-
NMR) and enantiopurity >99% ee (tR = 4.86 min (S) and 11.37min (R)).
1H NMR (600 MHz, DMSO-d6): δ = 12.67 (s, 1H), 7.91 (d, J = 7.5 Hz, 2H),
7.73 (dd, J = 7.4, 4.8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.4 Hz,
2H), 7.34 (tt, J = 7.5, 1.4 Hz, 2H), 6.01 (s, 1H), 4.32 (dd, J = 9.6, 6.6 Hz,
1H), 4.28-4.18 (m, 2H), 3.91 (ddd, J = 10.3, 8.5, 3.7 Hz, 1H), 2.02 – 1.82
(m, 2H), 1.72-1.58 (m, 6H); 13C NMR (101 MHz, DMSO-d6): δ = 174.23,
156.30, 144.32, 141.19, 128.14, 127.54, 125.76, 120.60, 66.06, 62.24,
54.48, 53.53, 47.16, 31.02, 30.07; HRMS (ESI) calcd for C23H24NO5
[M+H]+: m/z = 394.16490, found: m/z = 394.16486.
Methyl
(S)-3-(3-acetylbicyclo[1.1.1]pentan-1-yl)-2-((tert-butoxy-
carbonyl)amino)propanoate (13b):
Compound 9b (2.18 g, 5.52 mmol), biacetyl (1.52 g, 17.6 mmol) and
tributyltin hydride (5.24 g,17.6 mmol) were dissolved in acetonitrile (370
mL). The resulting, slightly heterogenous solution was filtered and purged
with argon for 5 minutes. This solution was pumped with a Labomatic
HD3000 at 100 mL/min through 7 m of FEP tubing (3.1 mm OD, 2.7 mm
ID, volume 40 mL) that was wrapped in a single layer around a large
quartz immersion well (Photochemical Reactors Ltd., article number
3230) equipped with a 400 W medium pressure mercury lamp in a
borosilicate filter. The reaction solution leaving the photoreactor was re-
circulated for 2 h until LC/MS indicated full conversion. The reaction
mixture was extracted with heptane (3 x 150 mL) and the acetonitrile
phase concentrated under vacuo to yield 3.15 g of a yellow oil, which
was purified by chromatography on 340 g silica gel (EtOAc/heptane 9:93
to 40:60), to give the title compound (1.16 g, 68%) as a yellow oil with a
purity of ca 70% by 1H-NMR, and which was used without further
purification. 1H NMR (600 MHz, DMSO-d6): δ = 7.26 (d, J = 8.2 Hz, 1H),
4.04 – 3.93 (m, 1H), 3.62 (s, 3H), 2.26 (s, 1H), 2.05 (s, 4H), 1.89 – 1.77
(m, 9H), 1.39 (s, 9H), 1.38 – 1.19 (m, 7H); 13C NMR (151 MHz, DMSO-
d6): δ = 210.42, 208.98, 205.43, 172.74, 155.17, 98.07, 82.93, 78.22,
51.83, 51.66, 51.05, 44.07, 36.96, 32.19, 28.17, 26.04, 24.05, 23.86
(major impurities included in spectra); HRMS (ESI) calcd for C16H26NO5
[M+H]+: m/z = 312.18055, found: m/z = 312.18051.
Acknowledgements
The authors would like to acknowledge the skilled support of Dr.
Peter Ertl for his help in identifying pairs in our chemical
collection, Caroline Radoch for the CHI(IAM) assay, Daniel
Gosling for the solubility measurements, as well as Dominik
Wiss, Evelyn Schueller, Thomas Ruppen, Heiner Schuetz and
Stephanie Rothe-Poellet for synthetic work.
Keywords: non-specific binding • bicycloalkyl • bioisostere •
imaging agent • liquid chromatography
Methyl
(S)-3-(3-acetoxybicyclo[1.1.1]pentan-1-yl)-2-((tert-butoxy-
carbonyl)amino)propanoate (14b):
References:
To a solution of 13b (640 mg, 2.1 mmol) in CH2Cl2 (60 mL) was added
mCPBA (816 mg, 4.7 mmol, 2.3 equiv.). The resulting clear, pink solution
was stirred at RT for 3 d (the pink color disappeared after 3 h). The light
yellow, clear solution was washed with 10% aq. Na2SO3 (100 mL)
followed by sat. aq. NaHCO3 (100 mL). The organic phase was dried
over anhyd Na2SO4, filtered and concentrated at 40°C to yield 0.5 g
yellow oil that was purified by flash chromatography on 12 g silica gel
(EtOAc/heptane 1:9 to 6:4) to give the title compound as a colorless oil
(450 mg, 67%) with a purity of >90% (1H NMR). 1H NMR (600 MHz,
DMSO-d6): δ = 7.26 (d, J = 8.4 Hz, 1H), 3.98 (td, J = 9.7, 9.2, 4.1 Hz, 1H),
3.62 (s, 3H), 2.04 – 1.85 (m, 11H), 1.39 (s, 9H); 13C NMR (151 MHz,
DMSO-d6) δ 172.58, 169.70, 155.16, 78.24, 62.34, 53.29, 52.16, 51.85,
31.93, 29.86, 28.16, 20.97; HRMS (ESI) calcd for C16H26NO6 [M+H]+: m/z
= 328.17547, found: m/z = 328.17545.
[1]
[2]
[3]
[4]
Y. P. Auberson, E. Briard, D. Sykes, J. Reilly, M. Healy. Chem. Med.
Chem. 2016, 11, 1415-1427.
F. Assmus, Frauke, A. Seelig, L. Gobbi, E. Borroni, P. Glaentzlin, H.
Fischer. Eur. J. Pharm. Sci. 2015, 79, 27-35.
A. Harrell, C. Sychterz, M.Y. Ho, A. Weber, K Valko, K. Negash.
Pharma Res. Per. 2015, 3(5), e00173.
a) A. F. Stepan, C. Subramanyam, I. V. Efremov, J. K. Dutra, T. J.
O’Sullivan, K. J. DiRico, W. S. McDonald, A. Won, P. H. Dorff, C. E.
Nolan, S. L. Becker, L. R. Pustilnik, D. R. Riddell, G. W. Kauffman, B. L.
Kormos, L. Zhang, Y. Lu, S. H. Capetta, M. E. Green, K. Karki, E.
Sibley, K. P. Atchison, A. J. Hallgren, C. E. Oborski, A. E. Robshaw, B.
Sneed, C. J. O’Donnell, J. Med. Chem. 2012, 55, 3414−3424; b) M. R.
Barbachyn, D. K. Hutchinson, D. S. Toops, R. J. Reid, G. E. Zurenko,
B. H. Yagi, R. D. Schaadt, J. W. Allison, Bioorg. Med. Chem. Lett. 1993,
3, 671; c) K. C. Nicolaou, D. Vourloumis, S. Totokotsopoulos, A.
Papakyriakou, H. Karsunky, H. Fernando, J. Gavrilyuk, D. Webb, A. F.
Stepan, ChemMedChem 2016, 11, 31-37; d) N. D. Measom, K. D.
Down, D. J. Hirst, C. Jamieson, E. S. Manas, V. K. Patel, D. O. Somers,
ACS Med. Chem. Lett. 2017, 8, 43-48; e) M. V. Westphal, B. T.
Wolfstädter, J.-M. Plancher, J. Gatfield, E. M. Carreira, ChemMedChem
2015, 10, 461-469.
(S)-2-amino-3-(3-hydroxybicyclo[1.1.1]pentan-1-yl)propanoic
(15b):
acid
Compound 14b (400 mg, 1.2 mmol) was dissolved in 4N HCl in 1,4-
dioxane (32 mL) and stirred at RT for 24 h in a 50 mL round bottom flask.
The reaction mixture was concentrated at 30°C, dissolved in 6N aq. HCl
(50 mL) and stirred at RT for 24 h and then at 40°C for 36 h.
Concentration of the reaction mixture in vacuo at 40°C resulted in crude
title compound as a dark red oil (300 mg), which was used without further
purification.
[5]
a) A. Almenningen, B. Andersen, B. A. Nyhus, Acta Chem. Scand.
1971, 25, 1217; b) O. Ermer, J. D. Dunitz, Chem. Comm. 1968, 10,
567-8; c) T. Yildirim, P. M. Gehring, D. A. Neumann, P. E. Eaton and T.
Emrick, Carbon, 1998, 36, 809-815.
(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-hydroxybi-
cyclo[1.1.1]pentan-1-yl)propanoic acid (16b):
[6]
[7]
Z. Jiang, J. Reilly, B. Everatt, E. Briard, J. Pharm. Biomed. Anal. 2011,
54, 722–729.
K. Valko, C.M. Du, C.D. Bevan, D.P. Reynolds, M.H. Abraham. J.
Pharm. Sci. 2000, 89(8), 1085-96.
8
This article is protected by copyright. All rights reserved.