Tetrahedron Letters
Lewis acid facilitated regioselective synthesis of s-histidinoalanine
a
a
a
b
Ju Wu a, Bing Ma a, , Yuehui Wang , Yue Zhang , Shenghu Yan , Steven L. Castle
⇑
a School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou 213164, PR China
b Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
s
-Histidinoalanine, with an unusual cross-link between His and Ala, is the central component of
Received 28 January 2014
Revised 31 March 2014
Accepted 3 April 2014
Available online 13 April 2014
theonellamides, a family of bioactive peptidic natural products. Previous syntheses of this residue were
plagued with low regioselectivity in the alkylation step. Herein, we report two novel routes to
s
-histidinoalanine, involving alkylation of Boc-His-OMe with a serine-derived b-lactone and b-bromoala-
nine, respectively, as the electrophiles. The use of Mg(OTf)2 as a catalyst was found to be essential to
ensure high regioselectivity for the -isomer, presumably due to the formation of a six-membered ring
chelation involving the -nitrogen atom of histidine.
s
Keywords:
p
s-Histidinoalanine
Ó 2014 Elsevier Ltd. All rights reserved.
Theonellamide F
Magnesium triflate
Regioselective N-alkylation
Theonellamide F1 (1, Fig. 1) belongs to a family of unusual cross-
linked bicyclic dodecapeptides which were isolated from marine
sponges of the Theonella genus.2 Compound 1 was shown to induce
formation of large acidic vacuoles in rat embryonic fibroblasts.3 It
was also found to possess antifungal activities attributable to its
ability to bind 3b-hydroxysterols such as ergosterol.4 Theonella-
mides contain several unnatural amino acids, the most notable
low (13% from D
-Ser, 7% from His-OMe),10 thereby limiting the
amount of material available for total synthesis efforts.
Recently, Taylor group reported a highly regioselective synthe-
sis of s-histidinoalanine based on the alkylation of Boc-His-OMe
with a cyclic sulfamidate eletrophile.13 The main drawback of their
method lies in the need for excess histidine nucleophile (3 equiv)
along with the moderate yield in the alkylation step (57%), as well
as the challenges in the purification of the sulfamidate alkylating
reagent.13 Accordingly, we initiated our own efforts in the
one being
s-
L
-histidine-
D
-alanine (
s
-histidinoalanine), a bis-amino
-nitrogen and the Ala
-regio-
acid with a cross-link between the His
s
b-carbon. Additionally,
s
-histidinoalanine, along with its
p
synthesis of
We hypothesized that the low regioselectivity of the
Hamada–Shiori synthesis of -His- -Ala could be improved by
s-histidinoalanine.
isomer, is produced during the processing of milk products.5 Both
isomers have also been detected in human tissues such as dentin6
and cataractous human lens.7
s-
L
D
enlisting a Lewis acid. Presumably, a bidentate Lewis acid would
Despite their promising biological activities and unique molec-
ular architecture, there has been no reported total synthesis on
theonellamides. Indeed, only two groups disclosed synthetic
efforts toward theonellamides. In the 1990s, Hamada and Shioiri
reported preparation of Aboa8 and Ahad9 residues of theonella-
mide F. Their work ultimately culminated into the successful
construction of the left-hand10 and right-hand11 macrocycles.
Unfortunately, there has been no report on the completion of theo-
nellamide F; this may be partially attributed to the difficulties in
form a six-membered ring chelation with a suitably protected
His derivative, thereby preventing the
p
-N atom from functioning
CO2H Ahad
OH
H
N
β-Ala
O
O
allo-Thr
O
NH
O
NH
H2N
NH
O
HN
OH
NH
O
β
-OHAsn
HN
OH
OH
O
preparing the s-L-His-D-Ala. Hamada and Shioiri’s route (Scheme 1)
BrPhe
N
O
O
was based on a b-lactone ring-opening strategy12 which suffered
τ-L-His-
O
N
HN
D-Ala
from poor regioselectivity and the need for excess Boc-His-OMe
H2N
NH
NH
O
(5 equiv). Accordingly, the overall yield of
s-
L
-His-
D
-Ala remains
Aboa
O
O
HN
HO
Br
N
O OH
H
Br
1
⇑
Corresponding author. Tel.: +86 519 8633 4596; fax: +86 519 8633 4598.
Figure 1. Theonellamide F.
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.