Lewis acid facilitated regioselective synthesis of τ-histidinoalanine

Article abstract of DOI:10.1016/j.tetlet.2014.04.008

τ-Histidinoalanine, with an unusual cross-link between His and Ala, is the central component of 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 τ-histidinoalanine, involving alkylation of Boc-His-OMe with a serine-derived β-lactone and β-bromoalanine, respectively, as the electrophiles. The use of Mg(OTf)₂ as a catalyst was found to be essential to ensure high regioselectivity for the τ-isomer, presumably due to the formation of a six-membered ring chelation involving the π-nitrogen atom of histidine.

Full text of DOI:10.1016/j.tetlet.2014.04.008

Tetrahedron Letters 55 (2014) 3114–3116
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
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.
E-mail address: mabing79@gmail.com (B. Ma).
Figure 1. Theonellamide F.
http://dx.doi.org/10.1016/j.tetlet.2014.04.008
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

J. Wu et al. / Tetrahedron Letters 55 (2014) 3114–3116
3115
CO Me
2
CO Me
BocHN
2
BocHN
N
1) Boc-His-OMe (5 equiv.)
ACN, 5 days
O
N
t-BuO C
2
+
2) N,N'-di-i-Pr-O-t-Bu-isourea
N
CbzHN
O
CbzHN
t-BuOH, CH Cl
2
2
N
t-BuO C
2
NHCbz
π-L-His-D-Ala, 21%
τ-L-His-D-Ala, 40%
Scheme 1. Hamada–Shioiri synthesis of histidinoalanine.
CO2Me
H
N
Boc
LA
N
N
H
Figure 2. Proposed binding model.
only be accomplished by means of careful preparative TLC. This
observation underscores the difficulty in employing the
Hamada–Shioiri protocol to access complex natural products such
as 1.
OH
OH
CbzHN
O
a
b
O
H2N
COOH
2
CbzHN
CbzHN
COOH
3
4
To evaluate our hypothesis regarding the impact of Lewis acids
on the regioselectivity of histidine alkylations, readily available
salts Mg(OTf)2 and Zn(OTf)2 were tested. These Lewis acids were
found to slowly dissolve upon addition to a solution of Boc-His-
OMe in either acetonitrile, DMF, or acetone. However, they were
only partially soluble without Boc-His-OMe. These observations
suggest that the Lewis acids indeed bind to the histidine derivative.
Subsequent investigations of the alkylation reaction focused on
DMF and acetone as solvents due to their better ability to dissolve
the His–Lewis acid complex than acetonitrile.
c
OH
OH
Br
d
e
H2
N
COOMe
5
COOMe
CbzHN
COOMe
6
7
HCl
Scheme 2. Reagents and conditions: Synthesis of electrophiles 4 and 7. (a) Cbz-Cl,
THF, aq NaHCO3, rt, 12 h, 96%; (b) DIAD, PPh3, À78 °C, THF, 57%; (c) SOCl2, MeOH,
À10 °C, 7 h, 90%; (d) Cbz-Cl, THF, aq NaHCO3, rt, 12 h, 91%; (e) PPh3, CBr4, CH2Cl2, rt,
9 h.
Optimization of the alkylation with b-lactone 4 is summarized
in Table 1. Although Zn(OTf)2 was a competent Lewis acid,
Mg(OTf)2 led to higher yields and cleaner mixtures, prompting us
to examine the latter Lewis acid in more detail. In either DMF or
as a nucleophile and directing the alkylation site to the
(Fig. 2). Herein, we report our findings that Mg(OTf)2 is capable
of mediating the construction of -His- -Ala via a highly regiose-
lective alkylation of Boc-His-OMe with either b-lactone or b-
bromoalanine electrophiles.
s-N atom
s-
L
D
acetone, moderate regioselectivities (2.5–4.5:1
s:p) and good
yields were obtained with either 1 or 2 equiv of 4. Surprisingly,
the use of an acetone–DMF 3:1 solvent mixture furnished excellent
The electrophiles used in this study are both readily accessible
from D
-Ser (2), and their synthesis is illustrated in Scheme 2.14,15
regioselectivity (20:1
this solvent mixture without
regioselectivity (2.5:1 ). Presumably, the finely tuned polarity
s:p
) and good yield. Alkylations conducted in
Initially, we repeated the Hamada–Shioiri protocol by treating 4
with excess Boc-His-OMe in the absence of a Lewis acid. Our re-
sults were virtually identical to the published results (cf. Scheme 1).
a
Lewis acid afforded low
s:p
of the mixed solvent system favors formation of the desired His–
Only a partial separation of the
s and p isomers was achieved via
Mg2+ complex. It is noteworthy that only a small excess (2 equiv)
flash chromatography, and in our hands complete separation could
Table 1
s
-L-His-D-Ala synthesis via b-lactone approach
CO2Me
CO2Me
BocHN
1. Lewis acid
BocHN
solvent
CbzHN
O
N
+
N
2. TMSCHN2
N
O
N
H
CbzHN
CO2Me
4
9
8
Entry
Solvent
Molar ratio (8:4:Mg2+
)
Regioselectivity (
s:
p
)
Yield (%)
1
2
3
4
5
6
7
8
9
ACN
ACN
DMF
DMF
1:1:1
2:1
2:1
2.5:1
2.5:1
4:1
45
<10
63
35
57
67
50
66
78
1:1:1 (Zn2+
1:1:1
)
)
1:1:1 (Zn2+
1:2:1
1:1:1
1:2:1
1:2:1
DMF
Acetone
Acetone
Acetone–DMF (3:1)
Acetone–DMF (3:1)
4:1
4.5:1
20:1
2.5:1
1:2:0

3116
J. Wu et al. / Tetrahedron Letters 55 (2014) 3114–3116
Table 2
s
-L-His-D-Ala synthesis via b-bromoalanine approach
Lewis acid
DMAP
Br
8
+
9
solvent
CbzHN
COOMe
7
Entry
Solvent
Molar ratio (8:7:Mg2+:DMAP)
Regioselectivity (
s
:
p)
Yield (%)
1
2
3
4
Acetone
Acetone
Acetone
Acetone
1:2:0:0
1:2:0:0.1
1:2:1:0
2.5:1
2.5:1
4:1
48
69
57
44
1:2:1:0.1
20:1
of electrophile 4 was employed, and purification of the adduct 9
was not adversely impacted by the presence of unreacted 4.
Table 2 summarizes our investigation of alkylation reactions
employing b-bromoalanine derivative 7 as the electrophile. Treat-
ment of 7 with 8 in the absence of a Lewis acid led to low regiose-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.04.008.
lectivity (2.5:1
s:p) and substantial quantity of an elimination
byproduct. The use of DMAP as a catalyst accelerated the alkylation
step and improved the yield of 9, but had no effect on the regiose-
lectivity. Employing Mg(OTf)2 in the absence of DMAP slightly im-
References and notes
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proved the
s:p ratio. Finally, a much higher regioselectivity (20:1
s:p
) was realized by combining the Lewis acid with DMAP. While
the precise role of DMAP is unclear, it may be activating the electro-
phile 7, thereby favoring substitution at the expense of elimination.
The positive impact of DMAP on the regioselectivity of the
Mg(OTf)2-promoted alkylation underscores the subtleties of the Le-
wis acid effect. Interestingly, complex mixtures were obtained from
reactions conducted in DMF or acetone–DMF solvent mixtures.
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In summary, two protocols for the regioselective synthesis of
histidinoalanine were developed. Both b-lactone and b-bromoala-
nine electrophiles afforded -His- -Ala in high regioselectivity
and moderate to good yields. Mg(OTf)2 was found to be the optimal
Lewis acid, and it presumably forms a six-membered ring chelation
s-
s
-L
D
involving the
p-nitrogen atom of His. Optimization of the reaction
solvent was critical to achieve high
s:p
selectivity. Importantly,
the requirement of a large excess of histidine was eliminated, which
significantly simplified the purification of product. Investigations of
Lewis acid promoted regioselective alkylation reactions of histidine
by other electrophiles are currently underway in our laboratory.
Acknowledgment
The authors thank the China National Science Foundation
(21102010) for support of this work.