Tetrahedron Letters
Synthesis of nitrocyclopropyl peptidomimetics
⇑
Norma K. Dunlap , Jacob Basham, Matthew Wright, Katrina Smith, Omar Chapa, Jihun Huang
Will Shelton, Yaroslav Yatsky
Middle Tennessee State University, Department of Chemistry, Murfreesboro, TN 37132, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Nitrocyclopropanation of amino-acid derived enones has led to a series of cyclopropyl peptidomimetics
suitable for further elaboration to compounds with the potential for biological activity.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 9 September 2013
Accepted 21 September 2013
Available online 27 September 2013
Keywords:
Nitrocyclopropanation
Peptidomimetic
Cyclopropane
Weinreb amide
The cyclopropane ring is found in numerous compounds, both
naturally occurring and synthetic. These include terpenes,
pheromones, and unusual amino acids, as well as synthetic anti-
bacterials, and conformationally restricted neurotransmitters.1
Cyclopropyl peptidomimetics have been reported to have anti-tu-
mor, antiviral, and antidepressant activities.2,3 While a number of
compounds include the cyclopropyl as a spiro or N-substituent,
there are relatively few examples incorporating the cyclopropane
into the backbone of peptidomimetics, introducing a degree of
rigidity to these flexible structures. Examples include Wipf’s cyclo-
propyl dipeptide isostere, Martin’s HIV protease inhibitor and the
anti-tumor natural product Belactosin A which, while not a pepti-
domimetic, contains a cyclopropyl amino acid (Fig. 1).4–8
We previously reported the synthesis of a core structure of
cyclopropyl peptidomimetics from protected amino acid Weinreb
amides. The core is variable at three positions, allowing diversifica-
tion of the template to a number of possible compounds.9
As shown in Figure 2, the central R1 group is defined by the
starting amino acid, deprotection of the terminal amine allows
for introduction of amides (R2) on the ‘left side’, and an ethyl ester
affords a handle for functionalization on the ‘right side’ of com-
pound 1. An efficient approach to ester-cyclopropyl precursors of
1, based on a sulfur-ylide cyclopropanation of amino-acid derived
enones was reported previously.9 Reported here is the extension of
this methodology to afford nitrocyclopropyl peptidomimetics,
allowing access to 2, and increasing the versatility of the ‘right-
side’ variations (R3).
which contains a bicyclic aminocyclopropane.10 Since that time,
the reaction has been investigated by Bellini, and an enantioselec-
tive version by Ley has been reported, mostly for cyclic enones,
with several examples of acyclic substrates.11,12 Following Ballini’s
procedure, addition of bromonitromethane to a solution of the en-
one 3 in acetonitrile, with freshly ground potassium carbonate as
base, afforded nitrocyclopropyl ketone 7 as a mixture of syn and
anti diastereomers (Fig. 3).
The synthesis of nitrocyclopropyl analogs of a series of amino
acids is summarized in Table 1.
Stereoselectivity in the nitrocyclopropanation is low, at approx-
imately 2:1 for most of these compounds, based on HPLC. This is
similar to the lack of selectivity seen in the ester series. Assignment
of stereochemistry is based on analogous behavior to the ester ser-
ies. In that series, absolute configuration of a derivative of the
phenylalanine product was established by X-ray crystallography.
As in the ester series, there is a consistent trend where the syn iso-
mers elute first on HPLC, and have a much higher positive optical
rotation. No racemization occurs during the cyclopropanation, as
evidenced by chiral SFC analysis of the valine analog 7c.
Reduction of the nitro group proved to be difficult, with so-
dium borohydride combinations (boride reductions) and alumi-
num hydride reductions resulting in decomposition.14–16
Selective removal of the Cbz protecting group was carried out
by palladium catalyzed hydrogenation to afford the nitro amine
9a. This allows for selective derivatization of the ‘left side’ of
the peptidomimetic. Reduction of both the nitro group and re-
moval of the Cbz protecting group afforded the unstable di-amine
10a, using either Raney nickel or transfer hydrogenation with a
48 h reaction time.17–19
Nitrocyclopropanation using bromonitromethane was first re-
ported for a synthesis of the antibacterial quinolone trovafloxacin,
For example, in the leucine series, cyclopropanation of the
enone 3a with EDSA, followed by ketone reduction afforded the
⇑
Corresponding author.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
Dunlap, Norma K.
