Organic Letters
Letter
a
Scheme 1. Synthesis Route to Chiral PTCs 9
Figure 1. Classic C2-symmetric chiral ligands and PTCs.
promoted cascade reactions with 91% yield. Subsequently, an
optical resolution was conducted using L-menthyl chloroformate
as a resolving agent, giving enantioenriched (R)-1 with >99% ee.
After that, Friedel−Crafts reaction, Duff reaction, retro-
Friedel−Crafts reaction, and esterification were performed
sequentially with high to excellent yields, and the desired
bistriflate 6 was obtained successfully. The above-mentioned
reactions were run according to the reported procedures in the
literature19 with slight modifications. Then the Pd-catalyzed
Suzuki coupling of bistriflate 6 with several arylboronic acids
afforded compounds 7 with 92−99% yields. In this step, three
different methods were used to introduce nine aryl groups at the
6,6′-positions of intermediates 7. The 3,5-bis(trifluoromethyl)-
phenyl and 3,4,5-trifluorophenyl were installed using method A,
the phenyl, 2-naphthyl, 4-phenylphenyl, 3,5-diphenylphenyl,
and 4-(2-naphthyl)phenyl were installed using method B, and
the 3,5-di-tert-butylphenyl and 4-tert-butylphenyl were installed
using method C. The subsequent reduction of 7 with NaBH4
followed by bromination of the resulting alcohols gave bromides
8 in almost quantitative yields, respectively. It was found that
using either PBr3 or CBr4/PPh3 as bromination reagents gave
the brominated products in low yields only. Finally, the reactions
of bromides 8 with secondary amines, including di-n-butyl-
amine, morpholine, and tetrahydropyrrole, delivered the
corresponding spirocyclic quaternary ammonium salts 9 with
excellent yields. Notably, employing NaHCO3 as base is key to
this step, and when using either K2CO3 or Na2CO3 instead of
NaHCO3, the compounds 8 will be decomposed. Considering
the solubility of compounds 8, the mixed solvents were used in
some cases (method E for 9c and 9n). Thus, 16 new spirocyclic
PTCs 9a−9p were synthesized successfully in 12 steps from
bisphenol A with 22−25% total yields (Figure 2a), and every
step can be conducted on a multigram scale. The X-ray crystal
structures of 9c and 9n clearly indicate that the absolute
configuration of this type PTCs is R and their dihedral angles are
65.3° and 64.5°, respectively (Figure 2b), which are smaller than
that of Maruoka PTCs.20
a
Conditions: (a) CH3SO3H, rt, 91%; (b) Et3N, DMAP, L-menthyl
chloroformate, CH2Cl2, rt, 95%; (c) recrystallization for three times at
t
−18 °C, 56%; (d) KOH, EtOH, reflux, 99%; (e) BuOH, CH3SO3H,
CH2Cl2, rt, 99%; (f) HMTA, TFA, AcOH, 4 M aq HCl, H2O, reflux,
71%; (g) AlCl3, CH3NO2, toluene, rt, 83%; (h) Tf2O, pyridine,
CH2Cl2, rt, 94%; (i) Method A: ArB(OH)2, Pd(PPh3)4, KBr, K3PO4·
3H2O, DME/H2O = 3/1, reflux, 92−95%; Method B: ArB(OH)2,
Pd(PPh3)4, K2CO3, DMF, 70 °C, 92−99%; Method C: ArB(OH)2,
Pd(PPh3)4, CH3OH/2 M aq K2CO3/THF = 1/2.5/25, reflux, 99%;
(j) NaBH4, THF/CH3OH = 1/1, 0 °C; (k) 33 wt % HBr in AcOH,
reflux; (l) Method D: R2NH, NaHCO3, CH3CN, 70 °C, 93−99%;
Method E: R2NH, NaHCO3, CH3CN/CHCl3 = 1/1, 70 °C, 92−98%.
active unnatural α-amino acids21 and viewed as a benchmark
reaction in asymmetric phase-transfer catalysis.2e Initially, the
PTCs 9a−9i bearing two n-butyl groups attached to the N atom
were tested at 2 mol % catalyst loading in Et2O using 50% aq
KOH as base at 0 °C (Table 1, entries 1−9). To our
disappointment, the target product 12a was delivered with
moderate to high yields but in low enantioselectivities. Even
worse, the enantioselectivities seemed so elusive. Consequently,
it was imperative to adjust the PTCs’s alkyl substituents at N
atom. When the catalyst was changed to 9j derived from
morpholine, the enantioselectivity of 12a was elevated
dramatically from 4% ee to 60% ee (entry 8 vs entry 10).
Then the use of toluene as solvent instead of Et2O gave a slightly
increased ee value (entry 11). To our surprise, the
tetrahydropyrrole-derived catalyst 9k containing similar rigid
N-spirocycle was found to be invalid for enhancing the
stereoselectivity (entry 12). Next, the morpholine-derived
catalysts 9l−9p were screened (entries 13−17), and it was
In order to evaluate the catalytic performance of the newly
synthesized spirocyclic PTCs, we applied them to the
enantioselective alkylation of tert-butyl glycinate Schiff base
(10) with benzyl bromide (11a), which was an entry to optically
2891
Org. Lett. 2021, 23, 2890−2894