10.1002/ejoc.202100748
European Journal of Organic Chemistry
FULL PAPER
Typical procedure for the Pd-catalyzed allylic amination (Table 1,
entry 3): In a glovebox a Schlenk tube was charged with [Pd(allyl)Cl]2
(14.2 mg, 38.3 µmol) and ligand L3* (73.0 mg, 95.2 µmol). Outside the
glovebox the Schlenk tube was connected to an argon line before dry THF
(1.0 mL) was added, and the solution was stirred for 20 min at room temp.
Then, carbonate rac-5a (441 mg, 1.93 mmol) was added neat by means
of a syringe and after 20 more min the amine 4b (500 mg; 3.81 mmol) was
added and stirring was continued for 18 h at room temp. After addition of
a small amount of Quadrasil® AP and stirring for 1 h the solution was
filtrated over a pad of Celite® with EtOAc and the solvent was removed
under reduced pressure. The crude product was purified by column
chromatography (CyHex/EtOAc 10:1, SiO2) to afford 497 mg (1.75 mmol;
91%) of (R)-10a as a yellow oil. The enantiomeric puritiy (80% ee) was
determined by GC FID) on a chiral Mega-DEX B-SE capillary column with
Conclusion
In conclusion we have elaborated a greatly improved protocol for
the synthesis of MediPhos ligands, including those with bulky alkyl
substituents. Furthermore, we could demonstrate that two of the
prepared C2-symmetric chiral diphosphines (L3* and L8*) perform
particularly well in the enantioselective Pd-catalyzed N-allylation
of tert-butyl glycinate (4b) using allyl methyl carbonates rac-5a
and rac-5b, respectively. Under optimized conditions, the allylic
amines 10a and 19b were obtained with up to 96% ee. The
usefulness of the developed protocol was proven in the stereo-
selective synthesis of H[ProM-17]OMe and H[ProM-21]OMe, two
novel conformationally restricted proline-derived dipeptide
building blocks for the construction of anti-metastatic EVH-1
inhibitors.[5c] We are optimistic, that the readily accessible
MediPhos ligands will find future application in asymmetric
transition metal catalysis.
H2 as carrier gas.1H NMR (500 MHz, CDCl3):
δ [ppm] = 5.49 (dt,
3J = 14.8 Hz, 3J = 7.1 Hz, 1H), 5.09 (ddt, 3J = 15.2 Hz, 3J = 8.8 Hz,
4J = 1.4 Hz, 1H), 3.39 – 3.17 (m, 2H), 3.01 (td, 3J = 8.2 Hz, 3J = 6.4 Hz,
1H), 1.92 (Ψhd, 3J = 6.8 Hz, 4J = 1.4 Hz, 2H), 1.74 (s, 1H), 1.68 – 1.56 (m,
2H), 1.46 (s, 9H), 1.31 (ddd, 3J = 7.7 Hz, 3J = 6.4 Hz, 3J = 2.2 Hz, 2H),
0.93 – 0.85 (m, 12H); 13C NMR (125 MHz, CDCl3): δ [ppm] = 172.2; 133.7;
132.0; 81.0; 58.9; 49.3; 45.6; 41.8; 28.5; 28.3; 24.9; 23.4; 22.5, 22.4; HR-
MS (ESI): Calcd. ([M+H]+): 284.2584; Found: 284.2582; [α]589 = 12.1 °.(c
= 0.66 in CHCl3). In a similar fashion, the product (R)-10a was obtained
with 92% ee using ligand L8*.
Experimental Section
H-[ProM-17]-OMe: To a solution of the acid chloride 18 (prepared in situ
from 177 mg (0.74 mmol) of the corresponding acid with 0.12 mL
(0.91 mmol) of Ghosez‘s reagent in 1.0 mL of CH2Cl2 at 0°C for 1 h) were
subsequently added at 0 °C a solution of the allylic amine (R)-10a (192 mg;
0.68 mmol) in 1.0 mL of CH2Cl2 and DIPEA (0.13 mL; 0.76 mmol). The
mixture was stirred at room temp for 16 h before it was cooled to 0 °C and
10 mL of 10% citric acid were added. The aqueous phase was extracted
with CH2Cl2 (4 x 20 mL) and the combined organic phases were washed
with 20 mL of sat. NaHCO3 and brine, dried with MgSO4, and concentrated
under reduced pressure. The crude product was purified by column
chromatography (CyHex/EtOAc 5:1; SiO2) to afford 334 mg (0.66 mmol;
97%) of 19a as a yellow oil (for characterization, see the Supporting
Information).
A solution of dipeptide 19a (286 mg, 0.57 mmol) in 6.5 mL of toluene was
heated to 70 °C and ca. 5 mg batches of the Hoveyda Grubbs II catalyst
were added every hour under argon (all in all 57.5 mg, 84.4 μmol). After
13 h at 70 °C full conversion was observed (TLC). Then, activated charcoal
was added and the mixture was stirred for further 30 min before it was
filtrated through a small pad of Celite® and the solvent was removed under
reduced pressure. The crude product was purified by column chroma-
tography (CyHex/EtOAc 2:1; SiO2) to afford 193 mg (0.46 mmol; 81%) of
Boc[ProM-17]OtBu as a colourless solid (for characterization, see the
Supporting Information). Note: If the product is not absolutely colourless it
should be immediately re-dissolved in EtOAc and treated again with
activated charcoal to remove remaining traces of Ru compounds which
may cause oxidative decomposition.
Only selected experiments are described here. For full details see the
supporting Information.
Dibromide 16h (R = 3-pentyl): A flask was charged with 673 mg
(1.43 mmol) of the ditoslyate (R,R)-14, 906 mg (3.73 mmol) of 2-bromo-6-
(pent-3-yl)-phenol, 824 mg (5.96 mmol) of K2CO3 and DMF (5.0 mL). The
mixture was stirred for 48 h at 50 °C under argon. Then, the suspension
was diluted with H2O and the aqueous phase was extracted three times
with tert-butyl methyl ether. The combined organic layers were washed
with brine, dried with MgSO4 and the solvent was removed under reduced
pressure. The crude product was purified by column chromatography
(CyHex/EtOAc 50:1; SiO2) to afford 832 mg (1.36 mmol; 95%) of the 16h
as a colourless oil. 1H NMR (500 MHz, CDCl3): δ [ppm] = 7.37 (dd,
3J = 7.9 Hz, 4J = 1.5 Hz, 2H), 7.12 (dd, 3J = 7.8 Hz, 4J = 1.5 Hz, 2H), 6.98
(ψt, 3J = 7.8 Hz, 2H), 4.67 – 4.53 (m, 2H), 4.22 – 4.05 (m, 4H), 3.03 (tt,
3J = 8.9 Hz, 3J = 5.7 Hz, 2H), 1.68 (Ψtq, J = 13.5 Hz, 3J = 7.3 Hz, 4H),
1.54 (s, 6H), 1.53 – 1.45 (m, 4H), 0.78 (t, 3J = 7.4 Hz, 12H); 13C NMR
(125 MHz, CDCl3): δ [ppm] = 154.0; 141.7; 130.9; 126.7, 125.9. 125.9;
117.6; 110.2; 76.9; 73.1; 41.1; 29.4; 28.9; 27.3; 12.4; 12.2; HR-MS (ESI):
Calcd. ([M+Na]+): 633.1186; Found: 633.1191. [α]589 = 31.3° (c = 0.67 in
CHCl3).
MediPhos Ligand L8*: A solution of dibromide 16h (778 mg, 1.27 mmol)
in 13 ml of THF was treated with nBuLi (1.80 mL of a 2.45 M solution in n-
hexane; 4.41 mmol) at -78 °C and stirring was continued for 1 h at -78 °C
before ClPPh2 (1.00 ml, 5.41 mmol) was added. The mixture was allowed
to slowly warm to room temperature overnight (16 h) and was then filtered
through a pad of Celite® with EtOAc. After removal of the solvent under
reduced pressure, the crude product was purified by column chromato-
graphy (CyHex/EtOAc 100:1; SiO2) to afford 899 mg (1.09 mmol; 86%) of
the MediPhos ligand L8* as a colourless foam. 1H NMR (600 MHz, CDCl3):
δ [ppm] = 7.29 – 7.13 (m, 22H), 7.01 (ψt, 3J = 7.6 Hz, 2H), 6.49 (ddd,
A solution of Boc[ProM-17]OtBu (103 mg, 0.24 mmol) in 2.1 mL of MeOH
was was cooled to 0 °C before 0.20 mL (2.75 mmol) of SOCl2 were added.
The mixture was stirred at room temp until full consumption was observed
by TLC (12 h). The solvent was removed under reduced pressure and the
residue was dissolved in 20 mL of CH2Cl2. A weak stream of ammonia gas
was directed trough the solution for 20 min. The resulting solid (NH4Cl)
was filtered off and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography (CH2Cl2/MeOH
20:1; SiO2) to afford 59 mg (0.21 mmol; 87%) of H[ProM-17]OMe as a
colourless oil. 1H NMR (500 MHz, CDCl3): δ [ppm] = 5.90 (dt, 3J = 11.1 Hz,
3
3J = 7.5 Hz, JH,P = 4.0 Hz, 3J = 1.6 Hz, 2H), 4.25 (d, 3J = 10.3 Hz, 2H),
4.23 – 4.21 (m, 2H), 4.09 (d, 3J = 9.1 Hz, 2H), 3.02 (tt, 3J = 9.1 Hz,
3J = 5.6 Hz, 2H), 1.75 – 1.63 (m, 4H), 1.58 – 1.40 (m, 4H), 1.18 (s, 6H),
0.82 (t, 3J = 7.4 Hz, 6H), 0.76 (t, 3J = 7.4 Hz, 6H). 13C NMR (150 MHz,
CDCl3) δ [ppm] = 159.4, 159.3; 139.3, 139.2; 137.2, 137.1; 134.2, 134.0,
133.7, 133.5; 131.3, 131.2; 131.0; 128.5, 128.5, 128.4, 128.4, 128.3,
128.2; 125.0; 109.0; 75.5; 72.1, 72.1, 72.0; 39.7; 29.8, 28.7; 26.6; 12.4,
12.0. 31P NMR (243 MHz, CDCl3): δ [ppm] = -15.90 (s); HR-MS (ESI):
Calcd. ([M+H]+): 823.4039; Found: 823.4040; [α]589 = 59.4°(c = 0.50 g in
CHCl3).
3
4
4J = 2.4 Hz, 1H), 5.49 (dt, J = 11.1 Hz, J = 3.0 Hz, 1H), 4.75 – 4.70 (m,
1H), 4.46 (d, 3J = 11.9 Hz, 1H), 4.41 (d, 2J = 17.5 Hz, 1H), 3.99 (d,
2J = 17.6 Hz, 1H) 3.71 (s, 3H), 3.22 (dd, 3J = 9.5 Hz, 3J = 4.7 Hz, 2H), 3.11
(bs, 1H), 2.62 – 2.55 (m, 1H), 2.23 – 2.18 (m, 1H), 1.81 – 1.72 (m, 1H),
1.63 (ψdp, J = 13.2 Hz, 3J = 6.5 Hz, 1H), 1.55 – 1.42 (m, 2H), 0.96 (Ψdd,
J = 15.8 Hz, 3J = 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ [ppm] = 174.3;
170.3; 131.9; 130.3; 62.1; 52.3; 51.7; 45.4; 45.2; 43.7; 42.1; 32.5; 25.1;
5
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