This document describes the synthesis of [2.2.1]bicyclo-1,4-bisoxaoline ligands using diastereoselective alkylation reactions. The synthesis starts with esterification of the carboxylic acid groups, followed by alkylation with ethyl aluminum chloride to form the (R,R) and (S,S) ligands in high diastereomeric excess. The ligands are then functionalized through reactions with thionyl chloride and amines to introduce various substituents at R1. Deprotection yields the final ligands with defined stereochemistry and substituents at the backbone, sidechain, and R1 position.

1. Synthesis of [2.2.1]Bicyclo-1,4-Bisoxaoline Ligands
O
CO2H NaOH (R) CO2R* R* (S) CO2R* NaOH CO2H
EtOH, ∆ O
EtOH, ∆
85% yield O
CO2R* 1.2 eq. Et2AlCl *R 1.2 eq. Et2AlCl 85% yield
CO2H (R)
(S) CO2R* CO2H
-78o, > 5 hrs., Toluene O -78o, > 5 hrs., Toluene
(R,R) Ligand R* = D-Menthol 87% yield, 99% d.e. (S,S) Ligand
SOCl2
backbone backbone
CH2Cl2 R* = L-Menthol SOCl2
distillation CH2Cl2
R1 distillation
R1
O O R1 R1
OH O
∗ OH O
Cl H2N N ∗ OH OH
∗
HH N ∗ H2N
Cl o o N
∗
HH Cl
THF, -78 - 0 , Et3N OH N
∗
OH THF, -78o - 0o, Et3N Cl
O 68% yield over 2 steps O
R1 O 68% yield over 2 steps O
R1
SOCl2
SOCl2
benzene, ∆
benzene, ∆
49 - 75% yield
49 - 75% yield
O R1
R1 O R1
N O O
MeOH, H2O, NaOH Cl R1
N ∗ Cl MeOH, H2O, NaOH
HH N ∗ N
N 31 - 61% yield ∗
N HH ∗ 31 - 61% yield
R1 Cl N N
O Cl
O R1
R1 O O
(R,R)-(4'S) R1
(S,S)-(4'S)
Configuration
Configuration
Backbone, Sidechain, R1
Backbone, Sidechain, R1
O (S,S), (4'S), i-Pr
(R,R), (4'S), t-Bu R1 O
N R1 (S,S), (4'S), t-Bu
(R,R), (4'S), Ph
N (S,S), (4'S), Ph
(R,R), (4'R), Ph
N (S,S), (4'S), Bn
R1 N (S,S), (4'R), Ph
O R1
David A. Quincy - UNL O
(R,R)-(4'R)
(S,S)-(4'R)
May 1992 - Dec. 1995
Improved Synthesis of the Bisoxazoline Ligands
Original Route
O R1 R1
O O
R*
O (S) CO2R* NaOH SOCl2 OH OH
CO2H H2N ∗
N ∗
O EtOH, ∆ CH2Cl2 Cl
*R HH ∗
1.2 eq. Et2 AlCl 85% yield distillation Cl N
O (S) CO2R* CO2H THF, -78o - 0o, Et3N OH
-78o, > 5 hrs., Toluene
O 68% yield over 2 steps O
87% yield, 99% d.e. R1
Preparation time = 2 days
from diacid SOCl2
Ligand synthesis in 9 steps including dimenthylfumarate and amino alcohol preparation.
benzene, ∆
49 - 75% yield
R1
O
O
R1 Cl
N MeOH, H2O, NaOH N ∗
HH ∗
31 - 61% yield N
N Cl
R1 O
O R1
Quincy Improved Route
O R1
O
R*
O (S) CO2R* NaOH Isobutylchloroformate, OH
CO2H N ∗
O EtOH, ∆ THF, NMM, -10o HH
*R ∗
1.2 eq. Et2 AlCl 85% yield R1 N
O (S) CO2R* CO2H 95% yield, 4 hrs. OH
-78o, > 5 hrs., Toluene
OH O
87% yield, 99% d.e. H2N ∗ R1
PPh3, CCl4, Et3N
Ligand synthesis in 7 steps including dimenthylfumarate and amino alcohol preparation. CH3CN, 9 hrs.
66-89% yield SOCl2 , CH2Cl2
O Et3N, 0o, 8 hrs.
R1
N 62% yield
This step suggested by
David A. Quincy - UNL N Professor Nicholas Natale
May 1992 - Dec. 1995 R1 at the 1995 Chicago ACS meeting
O