Strain-‐Release Amination
Strain-release amination
Gianatassio, R.; Lopchuk, J. M.; Wang, J.; Pan, C-M.; Malins, L. R.; Prieto, L.; Brandt, T. A.; Collins, M. R.; Gallego, G. M.; Sach, N. W.; Spangler, J. E.; Zhu, H.; Zhu, J.; Baran, P. S.
Science 2016, 351, 241-246
John Milligan 1 Current Literature Wipf Group Mee ng- February 13, 2016
Bioisosteres of t-butyl or phenyl
R' R' replace with R'
R R R
replace with CF3 R R R SF5 R CF3 R
2
Meanwell, N. A. J. Med. Chem. 2011, 54, 2529-2591 Westphal, M. V.; Wolfstädter, B. T.; Plancher, J-M.; Ga ield, J.; Carreira, E. M. ChemMedChem 2015, 10, 461-469 Bicyclo[1.1.1] pentane as a Ph Bioisostere
3
Stephan, A. F.; et al. J. Med. Chem. 2012, 55, 3414-3424 JAK inhibitor (P izer)
H N N N N N
HN
4
Hayashi, K. et al. PCT Int. Appl. WO2013024895 (2013) JAK inhibitor (P izer)
H N N N N N difficult to synthesize NH2
amination HN
5 Original synthesis of amine
LiDBB; PhSH HN CO2 3
SPh CO2H NH2
6
Weiberg, K. B.; Waddell, S. T. J. Am. Chem. Soc. 1990, 112, 2194-2216 Other approaches
7 Baran et al.’s proposal
R R N R2NH
"strain release general method for amination" installing this motif!
8 Precedence for propellane opening
t-BuLi; CO2
Br CO2H
9
Della, E. W.; Taylor, D. K.; Tsanakisidis, J. Tetrahedron Le . 1990, 31, 5219-5220 Precedence for propellane opening
t-BuLi; CO2
Br CO2H
t-Bu CO2 t-Bu
Li CO2H
10
Della, E. W.; Taylor, D. K.; Tsanakisidis, J. Tetrahedron Le . 1990, 31, 5219-5220 Preparation of propellane
Br Br PhLi Cl Bu2O Cl –45 °C to 0 °C can be stored as a stock solution
11 Amine addition
R R i-PrMgCl•LiCl R R N N H THF, rt THF NR MgCl•LiCl rt to 90 °C 2 overnight
12 Results
R R N MgCl•LiCl
THF N (from Et2O rt–90 °C R R stock sol'n) overnight
OEt N N N N N Bn R Bn OEt Bn OBn Bn Bn
R = Bn, 62% 12% 51% 42% 46% R = Me, 48% R = Et, 64% R = i-Bu, 72%
N S N N N N Bn Et NBn 52% 74% 54% 54% O O 13 Results
R R N MgCl•LiCl
THF N (from Et2O rt–90 °C R R stock sol'n) overnight
N N N N N
N N Bn 32% 57% 53% 67% 69% OMe
N N N N Bn Bn Bn Bn N MeO N N O 14 54% 60% 39% 48% R R N MgCl•LiCl
THF N (from Et2O rt–90 °C R R stock sol'n) overnight
Cl F Cl
O
O O
N N N
"propellerized" "propellerized" "propellerized" maprotilline sertraline maprotilline 80% 62% 67%
Cl Cl
O
N N N N N N N
"propellerized" "propellerized" "propellerized" 15 lorcaserin quipazine amoxapine 84% 81% 31% Azetidine formation
Br PhLi Br NH2 N R –78 °C to rt R N
then Boc2O NBoc R R i-PrMgCl•LiCl R R N N H THF, rt MgCl•LiCl
16 Azetidine formation: results
R S OBn Bn N Bn N Bn N Bn N
NBoc NBoc NBoc NBoc
R = Me, 46% 45% 42% 50% R = Et, 44% R = iBu, 42%
BnN O
N N N
NBoc NBoc NBoc
52% 47% 58% 17 Azetidine formation: results
N N N
NBoc NBoc NBoc
60% 55% 43%
Ar
N N N NBoc NBoc N
"azetidinylated" "azetidinylated" NBoc quipazine sertraline 51% 45% "azetidinylated" nortriptyline 45% 18 Bicyclobutane formation
19 Bicyclobutane addition
One pot process:
O O O O R NH S F 2 S F o LiCl Mg R N DMSO, rt R MeOH N R F F R
20 Cyclobutane Results
One pot process:
O O O O R NH S F 2 S F o LiCl Mg R N DMSO, rt R MeOH N R F F R
Me Bn N H N Me N N N Bn R R Boc Me
97% R = Ph, 61% R = Ph, 73% 95% R = Bn, 40% R = Bn, 93%
N N O N N N Bn BnN 21 TBSO 68% 71% 60% 76% 75% Cyclobutane Results
One pot process:
O O O O R NH S F 2 S F o LiCl Mg R N DMSO, rt R MeOH N R F F R
F
CF3
O Ar Ph O Me Me Me N N N N
O O
"cyclobutylated" "cyclobutylated" "cyclobutylated" "cyclobutylated" 22 nortriptyline fluoxetine paroxetine sertraline 83% 61% 70% 67% Sulfone utility
O O D S F 1. CD3ONa, CD3OH D
Bn N 2. Na/Hg Bn N F 55% Bn Bn
O O S F 1. LHMDS, allyl bromide
Bn N 2. Mgo, MeOH Bn N F Bn 80% Bn 2.7:1 syn/anti
O O S F 1. LHMDS, F NFSI
Bn N 2. Na/Hg Bn N F 51% 7:1 syn/anti Bn Bn
O O 1. PhCHO, t-BuOK S F Ph 23 2. DMAP, Et3N, Ac2O
Bn N 3. Na/Hg Bn N F 63% Bn Bn Cyclopentanes
N OMs NH
n-BuLi LiCl O THF O O S DMSO, rt S S 50% O O 55% O F F F single diastereomer F F F
Bn N
BnN N NH
LiCl O O S DMSO, rt S O 42% O 24 F F ~12:1 syn/anti F F Peptide labeling
F O S O F SH H K2CO3 H-WTPY N N GHNK-OH clean thiol addition? H O DMF/H2O (1:2) 0.05 M, rt, 5 h
side chains include: imidizole (H) amine (K) phenol (Y) indole NH (W)
25 Peptide labeling
F O SO2Ar S O F SH S H K2CO3 H H-WTPY N H-WTPY N N GHNK-OH N GHNK-OH H H O DMF/H2O (1:2) O 0.05 M, rt, 5 h 91% side chains include: imidizole (H) amine (K) phenol (Y) indole NH (W)
HPLC trace:
26 Peptide labeling
Et O N O
SH H K2CO3 H-WTPY N N GHNK-OH product mixture H O DMF/H2O (1:2) 0.05 M, rt, 5 h
HPLC trace:
27 Peptide labeling
28 Kinetic studies
29 Conclusion
• A new, efficient method to produce the bicyclo[1.1.1] amine func on via addi on to propellane was developed • By its nature, this method is general to any secondary amine • The method was extended to bicyclobutanes and azabicyclobutanes • These reagents may be of use in bioconjuga on, pep de labeling, and stapled pep des
30