Tetrahedron Letters
SN2 displacement at the quaternary carbon center: a novel entry
to the synthesis of
a,a-disubstituted
a-amino acids
⇑
⇑
Kotaro Ishihara, Hiromi Hamamoto, Masato Matsugi , Takayuki Shioiri
Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel method for the SN2 reaction on quaternary carbon atoms using bis(p-nitrophenyl)phosphorazi-
Received 21 November 2014
Revised 5 January 2015
Accepted 6 January 2015
Available online xxxx
date has been developed. Chiral tertiary alcohols were directly converted into the corresponding chiral
tertiary azides with complete inversion of configuration. Several
a,a-disubstituted a-amino esters or
amino acids were prepared through the conversion of azides to the corresponding amines by catalytic
hydrogenation.
Ó 2015 Elsevier Ltd. All rights reserved.
This Letter is dedicated to the late Professor
Harry Wasserman, a great chemist as well as
a splendid artist
Keywords:
SN2 displacement
Quaternary carbon center
tert alcohols
Azidation
Bis(p-nitrophenyl)phosphorazidate
a,a-Disubstituted a-amino acids
Substitution by the SN2 mechanism proceeds by the attack of
reports dealing with the application to tertiary alcohols to date.
Thus, the application of p-NO2DPPA to the azidation of tertiary
alcohols would be appreciated. Herein, we report the user-friendly
and safe method for the direct conversion of tertiary alcohols into
azides, which culminates in a novel method for the synthesis of
the nucleophile to the reactant from the back side of the leaving
group, while simultaneously displacing the leaving group. It is
susceptible to the effect of steric hindrance. Generally it does not
occur at quaternary carbon atoms, because the nucleophile does
not attack from the back of sterically hindered reaction centers.
Instead, an SN1 reaction or elimination will occur. However, only
a few examples have been reported on the conversion of sterically
hindered tertiary alcohols to azides by using phenyl diphenyl-
a,a-disubstituted
a-amino esters or amino acids. Although a,a-
disubstituted -amino acids are non-proteinogenic, they are quite
a
important since they have characteristic features such as chemical
stabilization, enhancement of lipophilicity, restriction of confor-
mational freedom of peptides containing these amino acids.
We initially explored the azidation of racemic methyl atrolac-
tate (( )-1a) as a model substrate using p-NO2DPPA together with
l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in toluene. The reaction
using traditional conditions4 afforded the desired azide (( )-2a)
in low yield (entry 1 in Table 1). Optimization of the reaction con-
ditions was performed through the investigation of various equiv-
alents of reagents (entries 2–12 in Table 1). Then yields were
improved as increasing the quantities of p-NO2DPPA. The reaction
could proceed smoothly by using a slight excess of DBU, while the
use of a large excess of DBU was revealed to lower the yield.
Since the desired azide was obtained in high yield, the azidation
reaction was further optimized by investigating various solvents
and DPPA (diphenyl phosphorazidate) instead of p-NO2DPPA. It is
well known that the polar aprotic solvents are preferred solvents
in the SN2 displacement. However, the use of THF as a solvent
1
phosphinite and TMSN3 and the Mitsunobu reaction with HN3.2
These azidation reactions will proceed through an SN2 mechanism.
The application of these reactions is, however, neither convenient
nor necessarily safe owing to the use of highly toxic and explosive
azide sources.
On the other hand, bis(p-nitrophenyl)phosphorazidate (p-NO2
DPPA),3 an azidating agent, is suppressed explosibility due to sta-
bilization by the function of the phosphorus atom. Previously, it
was applied to the azidation of primary and secondary alcohols,
in which the reactions proceed via an SN2 mechanism and afford
azides with inversion of their stereochemistries.4 There are no
⇑
Corresponding authors. Tel.: +81 52 832 1151x6251; fax: +81 52 835 7450.
(T. Shioiri).
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.