Tetrahedron Letters 55 (2014) 3114–3116

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Lewis acid facilitated regioselective synthesis of s-histidinoalanine

Ju Wu a, Bing Ma a,⇑, Yuehui Wang a, Yue Zhang a, Shenghu Yan a, Steven L. Castle b
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 theonellamides, a family of bioactive peptidic natural products. Previous syntheses of this residue were
Revised 31 March 2014 plagued with low regioselectivity in the alkylation step. Herein, we report two novel routes to
Accepted 3 April 2014
s-histidinoalanine, involving alkylation of Boc-His-OMe with a serine-derived b-lactone and b-bromoala-
Available online 13 April 2014
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 s-isomer, presumably due to the formation of a six-membered ring
Keywords:
chelation involving the p-nitrogen atom of histidine.
s-Histidinoalanine
Theonellamide F
Ó 2014 Elsevier Ltd. All rights reserved.
Magnesium triflate
Regioselective N-alkylation

Theonellamide F1 (1, Fig. 1) belongs to a family of unusual cross- low (13% from D-Ser, 7% from His-OMe),10 thereby limiting the
linked bicyclic dodecapeptides which were isolated from marine amount of material available for total synthesis efforts.
sponges of the Theonella genus.2 Compound 1 was shown to induce Recently, Taylor group reported a highly regioselective synthe-
formation of large acidic vacuoles in rat embryonic fibroblasts.3 It sis of s-histidinoalanine based on the alkylation of Boc-His-OMe
was also found to possess antifungal activities attributable to its with a cyclic sulfamidate eletrophile.13 The main drawback of their
ability to bind 3b-hydroxysterols such as ergosterol.4 Theonella- method lies in the need for excess histidine nucleophile (3 equiv)
mides contain several unnatural amino acids, the most notable along with the moderate yield in the alkylation step (57%), as well
one being s-L-histidine-D-alanine (s-histidinoalanine), a bis-amino as the challenges in the purification of the sulfamidate alkylating
acid with a cross-link between the His s-nitrogen and the Ala reagent.13 Accordingly, we initiated our own efforts in the
b-carbon. Additionally, s-histidinoalanine, along with its p-regio- synthesis of s-histidinoalanine.
isomer, is produced during the processing of milk products.5 Both We hypothesized that the low regioselectivity of the
isomers have also been detected in human tissues such as dentin6 Hamada–Shiori synthesis of s-L-His-D-Ala could be improved by
and cataractous human lens.7 enlisting a Lewis acid. Presumably, a bidentate Lewis acid would
Despite their promising biological activities and unique molec- form a six-membered ring chelation with a suitably protected
ular architecture, there has been no reported total synthesis on His derivative, thereby preventing the p-N atom from functioning
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-
H CO 2H Ahad
mide F. Their work ultimately culminated into the successful N OH
β-Ala
construction of the left-hand10 and right-hand11 macrocycles. O
O O allo-Thr
NH O
Unfortunately, there has been no report on the completion of theo- NH O HN OH
nellamide F; this may be partially attributed to the difficulties in O H2N β-OHAsn HN
preparing the s-L-His-D-Ala. Hamada and Shioiri’s route (Scheme 1) NH OH OH NH
BrPhe N
O O
was based on a b-lactone ring-opening strategy12 which suffered O HN
τ- L-His-
N D-Ala O
from poor regioselectivity and the need for excess Boc-His-OMe H2N NH NH
(5 equiv). Accordingly, the overall yield of s-L-His-D-Ala remains O Aboa
Br O O HN
N O OH
HO 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

CO2Me
BocHN CO 2Me
BocHN
1) Boc-His-OMe (5 equiv.)
O ACN, 5 days N t-BuO2 C
+
CbzHN O 2) N,N'-di-i-Pr-O-t-Bu-isourea N N
t-BuOH, CH2Cl2 CbzHN
N
t-BuO 2C
NHCbz
τ- L-His-D -Ala, 40% π-L-His- D-Ala, 21%

Scheme 1. Hamada–Shioiri synthesis of histidinoalanine.

CO2 Me
Boc H
N
LA
N
N
H

Figure 2. Proposed binding model.

only be accomplished by means of careful preparative TLC. This

OH
a
OH
b CbzHN O observation underscores the difficulty in employing the
Hamada–Shioiri protocol to access complex natural products such
H2 N COOH CbzHN COOH O
2 3 4 as 1.
To evaluate our hypothesis regarding the impact of Lewis acids
c
on the regioselectivity of histidine alkylations, readily available
OH OH Br salts Mg(OTf)2 and Zn(OTf)2 were tested. These Lewis acids were
d e
found to slowly dissolve upon addition to a solution of Boc-His-
H 2N COOMe CbzHN COOMe CbzHN COOMe OMe in either acetonitrile, DMF, or acetone. However, they were
HCl 5 6 7
only partially soluble without Boc-His-OMe. These observations
Scheme 2. Reagents and conditions: Synthesis of electrophiles 4 and 7. (a) Cbz-Cl, suggest that the Lewis acids indeed bind to the histidine derivative.
THF, aq NaHCO3, rt, 12 h, 96%; (b) DIAD, PPh3, 78 °C, THF, 57%; (c) SOCl2, MeOH, Subsequent investigations of the alkylation reaction focused on
10 °C, 7 h, 90%; (d) Cbz-Cl, THF, aq NaHCO3, rt, 12 h, 91%; (e) PPh3, CBr4, CH2Cl2, rt, DMF and acetone as solvents due to their better ability to dissolve
9 h.
the His–Lewis acid complex than acetonitrile.
as a nucleophile and directing the alkylation site to the s-N atom Optimization of the alkylation with b-lactone 4 is summarized
(Fig. 2). Herein, we report our findings that Mg(OTf)2 is capable in Table 1. Although Zn(OTf)2 was a competent Lewis acid,
of mediating the construction of s-L-His-D-Ala via a highly regiose- Mg(OTf)2 led to higher yields and cleaner mixtures, prompting us
lective alkylation of Boc-His-OMe with either b-lactone or b- to examine the latter Lewis acid in more detail. In either DMF or
bromoalanine electrophiles. acetone, moderate regioselectivities (2.5–4.5:1 s:p) and good
The electrophiles used in this study are both readily accessible yields were obtained with either 1 or 2 equiv of 4. Surprisingly,
from D-Ser (2), and their synthesis is illustrated in Scheme 2.14,15 the use of an acetone–DMF 3:1 solvent mixture furnished excellent
Initially, we repeated the Hamada–Shioiri protocol by treating 4 regioselectivity (20:1 s:p) and good yield. Alkylations conducted in
with excess Boc-His-OMe in the absence of a Lewis acid. Our re- this solvent mixture without a Lewis acid afforded low
sults were virtually identical to the published results (cf. Scheme 1). regioselectivity (2.5:1 s:p). Presumably, the finely tuned polarity
Only a partial separation of the s and p isomers was achieved via of the mixed solvent system favors formation of the desired His–
flash chromatography, and in our hands complete separation could Mg2+ complex. It is noteworthy that only a small excess (2 equiv)

Table 1
s-L-His-D-Ala synthesis via b-lactone approach
CO2 Me
CO2 Me BocHN
1. Lewis acid
BocHN solvent
CbzHN O
N
+
N O 2. TMSCHN2 N
N
H CbzHN
CO2 Me
8 4 9

Entry Solvent Molar ratio (8:4:Mg2+) Regioselectivity (s:p) Yield (%)

1 ACN 1:1:1 2:1 45
2 ACN 1:1:1 (Zn2+) 2:1 <10
3 DMF 1:1:1 2.5:1 63
4 DMF 1:1:1 (Zn2+) 2.5:1 35
5 DMF 1:2:1 4:1 57
6 Acetone 1:1:1 4:1 67
7 Acetone 1:2:1 4.5:1 50
8 Acetone–DMF (3:1) 1:2:1 20:1 66
9 Acetone–DMF (3:1) 1:2:0 2.5:1 78
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
Br DMAP
8 + 9
CbzHN COOMe solvent
7

Entry Solvent Molar ratio (8:7:Mg2+:DMAP) Regioselectivity (s:p) Yield (%)

1 Acetone 1:2:0:0 2.5:1 48
2 Acetone 1:2:0:0.1 2.5:1 69
3 Acetone 1:2:1:0 4:1 57
4 Acetone 1:2:1:0.1 20:1 44

of electrophile 4 was employed, and purification of the adduct 9 Supplementary data

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-
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-
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.
In summary, two protocols for the regioselective synthesis of s-
histidinoalanine were developed. Both b-lactone and b-bromoala-
nine electrophiles afforded s-L-His-D-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
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
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.
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The authors thank the China National Science Foundation

(21102010) for support of this work.