Please cite this article in press as: Struntz et al., Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription, Cell
Methyl (5S)-5-(2-(azidomethyl)phenyl)-2-phenyl-4,5-dihydrooxazole-4-carboxylate (KI-MS2-082)
An oven-dried flask was charged with 5-methoxy-2-phenyloxazole (2.54 g, 14.51 mmol), 2-(azidomethyl)benzaldehyde (2.58 g,
15.96 mmol) and anhydrous 1:1 CH2Cl2:CH3CN (100 mL). The flask was purged with Arg, cooled to 0ꢁC and SnCl4 (17.6 mL,
1.0 M in CH2Cl2) was added. The reaction was stirred overnight at room temperature then cooled to 0ꢁC. Saturated NaHCO3
(100 mL) was carefully added followed by CH2Cl2 (75 mL) and the solution was vigorously stirred for 3 hr. The aqueous layer was
extracted with EtOAc (4 x 30 mL). The combined organic layers were dried over MgSO4, filtered concentrated and purified by
column chromatography (10 to 45% EtOAc in hexanes) to afford KI-MS2-082 (4.49 g, 92% yield) and as a mixture of diastereomers,
1
as a yellow oil. KI-MS2-082cis (higher Rf ) H NMR (500 MHz, CDCl3): d 8.10 (d, J = 8.0 Hz, 2H), 7.55 (m, 1H), 7.45-7.50 (m, 3H),
7.31-7.39 (m, 3H), 6.18 (d, J = 10.5 Hz, 1H), 5.35 (d, J = 10.5 Hz, 1H), 4.45 (d, J = 13.5 Hz, 1H), 4.37 (d, J = 13.5 Hz, 1H), 3.18
(s, 3H). 13C NMR (125 MHz, CDCl3): d 169.8, 167.0, 135.1, 132.7, 132.4, 129.7, 129.1, 129.0, 128.8, 127.0, 126.9, 79.9, 73.9, 53.1,
52.1. KI-MS2-082Trans (lower Rf) 1H NMR (500 MHz, CDCl3): d 8.08 (d, J = 8.0 Hz. 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.46 (t, J =
8.0 Hz, 2H), 7.34-7.40 (4H, m), 6.21 (d, J = 7.0 Hz, 1H), 4.79 (d, J = 7.0 Hz, 1H), 4.55 (d, J = 13.5 Hz, 1H), 4.46 (d, J = 13.5 Hz,
1H), 3.87 (s, 3H). 13C NMR (125 MHz, CDCl3): d 171.6, 165.8, 138.6, 132.5, 132.4, 130.5, 129.8, 129.1, 129.0, 128.7, 126.9, 126.4,
80.0, 77.3, 53.2, 52.6. HRMS (m/z): [M]+ calcd. for C18H16N4O3, 337.1295; found 337.1268.
( )-(4S,5S)-methyl 5-(2-(azidomethyl)phenyl)-4-benzyl-2-phenyl-4,5-dihydrooxazole-4-carboxylate (KI-MS2-006)
A cis/trans mixture of KI-MS2-082 (4.49 g, 13.35 mmol) was diluted in DMF (50 mL). BTPP (5.40 mL, 17.35 mmol) was then
added at room temperature followed by benzyl bromide (6.40 mL, 53.40 mmol), K2CO3 (3.69 g, 26.70 mmol) and TBAI
(2.46 g, 6.67 mmol). After 16 hr, the reacting mixture was concentrated and purified by column chromatography on
silica gel (5 to 40% EtOAc in hexanes) to afford KI-MS2-006 (5.28 g, 93% yield) as a 95:5 dr. 1H NMR (500 MHz, CDCl3):
d 8.04 (m, 2H), 7.54 (m, 1H), 7.46 (m 2H), 7.39 (m, 2H), 7.23-7.38 (m, 7H), 5.93 (s, 1H), 4.58 (d, J = 14.0 Hz, 1H), 4.45
(d, J = 14.0 Hz, 1H), 3.57 (d, J = 13.5 Hz, 1H), 3.45 (d, J = 13.5 Hz, 1H), 3.16 (s, 3H). 13C NMR (125 MHz, CDCl3): d 171.6,
165.0, 136.5, 135.2, 133.0, 132.2, 131.3, 130.0, 129.0, 128.8, 128.7, 128.4, 127.4, 127.2, 127.1, 84.7, 82.5, 53.0, 52.4,
45.0. HRMS (m/z): [M]+ calcd. for C25H22N4O3, 427.1652; found 427.1678. The other diastereomer (lower Rf) can also be
isolated. 1H NMR (500 MHz, CDCl3): d 8.18 (d, J = 7.5 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.46 (t, J =
7.5 Hz, 1H), 7.31-7.41 (m, 7H), 6.04 (s, 1H), 5.01 (d, J = 11.0 Hz, 1H), 4.74 (d, J = 14.5 Hz, 1H), 4.73 (d, J = 11.0 Hz, 1H),
3.15 (s, 3H).
( )-(3aS,10bS)-3a-benzyl-2-phenyl-5,6-dihydro-3aH-benzo[c]oxazolo[5,4-e]azepin-4(10bH)-one (KI-MS2-007)
KI-MS2-006 (1.73 g, 4.06 mmol) was diluted in THF:H2O (10:1, 100 mL) followed by addition of DBU (0.64 mL, 4.26 mmol) and
PMe3 (4.50 mL, 1.0 M in THF) at room temperature. After 16 hr, water was added and the aqueous layer extracted with
CH2Cl2 (x 3). The combined organic layers were dried over MgSO4, filtered concentrated and purified by column
chromatography on silica gel (0 to 15% MeOH in CH2Cl2) providing KI-MS2-007 (1.21g, 81% yield). 1H NMR (500 MHz,
CDCl3): d 8.11 (d, J = 9.0 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.36 (m, 2H), 7.16-7.32 (m, 7H), 5.84
(bs, 1H), 4.22 (m, 1H), 3.95 (dd, J = 15.5, 7.5 Hz, 2H), 3.51 (s, 2H). 13C NMR (125 MHz, CDCl3): d 180.1, 165.9, 138.3,
134.3, 133.5, 131.3 (2), 129.5 (4), 128.8 (2), 128.5 (2), 128.4 (2), 128.2 (2), 127.5, 83.1, 65.0, 44.1, 32.3. HRMS (m/z): [M]+ calcd.
for C24H20N2O2, 369.1598; found 369.1580.
e5 Cell Chemical Biology 26, 1–13.e1–e14, May 16, 2019