An atom-efficient direct regioselective N(τ)-allylation of histidine derivatives

Article abstract of DOI:10.1055/s-0032-1317669

Protected N(τ)-allylhistidine has been been prepared by the first direct regioselective allylation procedure using the sterically bulky N(α)-Boc protection group to shield N(π) and thereby inducing regioselectivity. This afforded the N(τ)-allyl protected

Full text of DOI:10.1055/s-0032-1317669

LETTER
▌2969
lAettner Atom-Efficient Direct Regioselective N(τ)-Allylation of Histidine
Derivatives
Regioselective Histidine N(τ)-Allylation
Nis Halland*
Sanofi-Aventis Deutschland GmbH, Industriepark Höchst Building G838, 65926 Frankfurt am Main, Germany
Fax +49(69)30521618; E-mail: Nis.Halland@sanofi.com
Received: 10.09.2012; Accepted after revision: 29.10.2012
generally found to be prepared by tedious multistep se-
quences. For instance Guibe et al. prepared N(α)-Boc-
N(τ)-allylhistidine methyl ester (1) by diallylating N(α)-
Abstract: Protected N(τ)-allylhistidine has been been prepared by
the first direct regioselective allylation procedure using the sterical-
ly bulky N(α)-Boc protection group to shield N(π) and thereby in-
ducing regioselectivity. This afforded the N(τ)-allyl protected Boc-histidine methyl ester followed by a palladium-cata-
histidine building block in excellent yields without loss of optical lyzed deallylation in the presence of allyl scavengers
1
purity.
(
method A, Scheme 1). This two-step procedure afforded
Key words: histidine, allylation, regioselectivity, amino acid, al- N(α)-Boc-N(τ)-allylhistidine methyl ester (1) in reason-
kylation
able yields but only a moderate regioselectivity of about
5:1 in favor of the N(τ)-allyl regioisomer 1 over the N(π)-
1
allyl regioisomer 2 was achieved.
During one of our recent drug-discovery programs we re-
quired significant amounts (>25g) of protected N(τ)-allyl-
histidine derivatives since the allyl group can be used for
further chemical transformations, for example, metathesis
reactions or as an attractive protecting group. To our sur-
prise a literature survey revealed no efficient or attractive
synthesis route to this simple building block which was
Jain et al. has presented a completely regioselective, four-
step synthesis of N(τ)-allylhistidine methyl ester as pre-
2
sented in Scheme 1 (method B). Since none of these pro-
cedures seemed attractive to us we decided to optimize the
direct allylation of N(α)-Boc-histidine methyl ester using
allyl bromide despite the fact that reported procedures
were quite unselective and afforded mixtures of the N(π)-
O
N
OMe
method A
N
NHBoc
Br–
N(τ)-allyl 1
O
O
Pd(PPh3)4
scavenger
allyl bromide
N
Na CO3
2
N
OMe
NHBoc
OMe
NHBoc
O
MeCN, 40 °C
CH2Cl2, reflux
N
N
N
OMe
N
NHBoc
N(π)-allyl 2
method B
I–
O
O
O
CDI
allyl iodide
N
N
OMe
OMe
OMe
N
N
+
DMF, 60 °C
N
NH
MeCN, reflux
N
NH
NH2
O
O
6
M HCl
100 °C
O
O
1
) HCl (g), MeOH
) NH3, MeOH
OH
OMe
N
N
N
N
2
NH2
2HCl
NH2
⋅
Scheme 1
SYNLETT 2012, 23, 2969–2971
Advanced online publication: 19.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317669; Art ID: ST-2012-B0762-L
Georg Thieme Verlag Stuttgart · New York
©

2970
N. Halland
LETTER
O
N
OMe
NHBoc
N
Br–
O
O
N(τ)-allyl 1
allyl bromide
N
N
OMe
NHBoc
+
+
OMe
+
N
N
NHBoc
O
3
N
OMe
NHBoc
N
N(π)-allyl 2
Equation 1
and N(τ)-allyl regioisomers (Equation 1) as well as the di- Table 1 Optimization of Reaction Conditions for the Allylation
3
2b
N(α)-Boc-histidine Methyl Estera
allylated salt 3 or no product at all.
In an attempt to improve the regioselectivity, N(α)-Boc-
histidine methyl ester was chosen as the bulky Boc group
was expected to increase the steric shielding of N(π) com-
pared to N(τ) and thus promote formation of the desired
N(τ)-allyl regioisomer 1. Furthermore the facile removal
of the Boc group under standard conditions at a later stage
in the synthesis was also of importance.
Yield of 1 (%)b
Entry
Base
Solvent
Time (h)
1
2
3
4
5
6
7
8
9
Et N
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
MeCN
MeCN
MeCN
20
20
20
20
20
3
<5
<5
<5
23
41
98
3
DBU
DABCO
Na CO
2
3
The initially attempted direct allylation under standard
conditions using allyl bromide (1.0 equiv) and K CO (2
K CO
2
3
2
3
equiv) in acetone proceeded sluggishly, and after 24 hours
only about 50% conversion was achieved and formation
of the diallylated byproduct 3 was observed. Raising the
temperature or the amount of allyl bromide to improve
conversion was only found to promote diallylation fur-
ther, and yields of the desired monoallylation product
were rarely above 50%. Although the different products
were easily separated by RP-HPLC this procedure was
highly inefficient in terms of yield and amounts of sol-
vents required for purification. We therefore initiated a
screening of reaction conditions in order to optimize the
reaction and initially screened the reaction with a number
of inorganic and organic bases in acetone at ambient tem-
perature. The results are presented in Table 1. Cs CO was
Cs CO
2
3
K PO
3
48
3
4
0c
NaOH
KOH
LiOH
NaOH
KOH
20
20
3
33d
11
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
0
3
0c
58d
3
Cs CO
Et O
20
3
45
16
95
63
<5c
83
98
98
2
3
3
3
3
3
3
3
3
2
Cs CO
CH Cl
2
2
2
2
2
3
Cs CO
CH Cl
20
20
20
20
3
2
2
found to be a superior base for the reaction affording full
conversion in only three hours with 1.0 equivalent allyl
bromide, whereas the other bases only afforded minor
amounts of allylated histidine if at all.
Cs CO
1,4-dioxane
MeOH
THF
2
Cs CO
2
Cs CO
We also screened a number of solvents using Cs CO as
2
2
3
the base and it was found that acetonitrile and DMF also
afforded full conversion to the desired monoallylation
product in a clean reaction in just a few hours (Table 1).
For practical reasons acetone was selected for further
Cs CO
DMF
2
2
Cs CO
MeCN
3
2
a
N(α)-Boc-histidine methyl ester (1.0 equiv) and base (2.0 equiv)
were suspended in the solvent, allyl bromide (1.0 equiv) was added,
work due to its low toxicity and easy removal. Under the
4
optimized reaction conditions a two gram test reaction af- and the reaction stirred at ambient temperature.
b
Determined by LC–MS.
forded the N(α)-Boc-N(τ)-allylhistidine methyl ester (1)
c
Complete hydrolysis of the methyl ester observed.
in 96.2% isolated yield with complete regioselectivity. No
d
Partial hydrolysis of the methyl ester observed.
N(α)-Boc-N(π)-allylhistidine methyl ester (2) was ob-
1
served by LC–MS or H NMR, and the diallylated by-
identity of the N(α)-Boc-N(τ)-allylhistidine methyl ester
1) a ROESY NMR was recorded which clearly showed
product 3 that was formed in 1.5–2% yield was removed
during the workup procedure. In order to confirm the
(
Synlett 2012, 23, 2969–2971
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective Histidine N(τ)-Allylation
2971
the isolated regioisomer to be the N(τ)-allylated isomer. It References and Notes
1
was also observed by H NMR that N(α)-Boc-N(τ)-allyl-
(
1) Kimbonguila, A. M.; Boucida, S.; Guibe, F.; Loffet, A.
Tetrahedron 1997, 53, 12525.
2) (a) Jain, R.; Cohen, L. A. Tetrahedron 1996, 52, 5363.
(b) Kaur, N.; Monga, V.; Jain, R. Tetrahedron Lett. 2004,
45, 6883.
histidine methyl ester (1) exists as a ca. 5.5:1 mixture of
rotamers at 300 K, and upon heating to 330 K or higher the
rotamers disappeared only to return when the sample was
cooled to 300 K again (see Supporting Information). The
presence of rotamers at 300 K is an indication that the ste-
ric bulk of the Boc group is so large that a very efficient
shielding of N(π) is present. This is in line with the exper-
imental results where no N(α)-Boc-N(π)-allylhistidine
methyl ester (2) is observed. The optical purity of the
N(α)-Boc-N(τ)-allylhistidine methyl ester (1) was deter-
mined to be >98% enantiomeric excess by HPLC using a
chiral stationary phase and thus not found to be compro-
mised during the allylation. In order to test the generality
of the reaction we also attempted the direct N(τ)-ben-
zylation of N(α)-Boc-histidine methyl ester using benzyl
bromide under the optimized reaction conditions. This af-
(
(
(
3) Jones, J. B.; Hysert, D. W. Can. J. Chem. 1971, 49, 3012.
4) Typical Procedure for the Allylation of N(α)-Boc-
histidine Methyl Ester
Commercially available N(α)-Boc-histidine methyl ester
(
1.0 equiv) and Cs CO (2.0 equiv) were suspended in
2 3
acetone, allyl bromide (1.0 equiv) was added, and the
reaction mixture was stirred at ambient temperature for 4 h.
The reaction mixture was filtered to remove the Cs CO and
2 3
evaporated to afford the crude N(α)-Boc-N(τ)-allylhistidine
methyl ester (1) which was purified by flash
chromatography on silica gel using EtOAc–heptane
mixtures as the eluent. This afforded the desired product as
a colorless oil in 96.2% after evaporation of the solvents.
Optical purity was determined by HPLC using a Chiralpak
5
forded the N(α)-Boc-N(τ)-benzylhistidine methyl ester in
IA stationary phase and a 1:1 mixture of EtOH and MeOH
1
as the eluent. H NMR (400 MHz, DMSO-d ): δ (major
85% isolated yield as a single regioisomer. Preliminary
6
rotamer) = 1.36 (s, 9 H), 2.80 (d, J = 6.5 Hz, 2 H), 3.58 (s, 3
H), 4.22 (q, J = 7.3 Hz, 1 H), 4.55 (d, J = 5.6 Hz, 2 H), 5.03
results of the direct alkylation of N(α)-Boc-histidine
methyl ester using n-propyl iodide, n-propyl bromide, and
n-propyl p-toluenesulfonate all afforded N(α)-Boc-N(τ)-
propylhistidine methyl ester as a single regioisomer in
(dd, J = 1.3, 17.1 Hz, 1 H), 5.17 (dd, J = 1.3, 10.2 Hz, 1 H),
5
.90–6.01 (m, 1 H), 6.83 (s, 1 H), 7.13 (d, J = 7.9 Hz, 1 H)
13
7.52 (s, 1 H). C NMR (150 MHz, DMSO-d ): δ (major
6
6
good to excellent yields. Therefore, it is expected that the
rotamer) = 28.1, 29.7, 48.3, 51.6, 53.7, 78.2, 116.8, 117.1,
+
scope of the reaction can be expanded to a variety of alkyl
halides, providing facile access to a broad range of N(τ)-
alkylated histidines.
134.5, 136.9, 137.1, 155.2, 172.5. MS (ES ): m/e calcd:
310.18 [M + H]; found: 310.22 [M + H].
(
5) N(α)-Boc-N(τ)-benzylhistidine Methyl Ester
1
H NMR (400 MHz, DMSO-d ): δ (major rotamer) = 1.34 (s,
6
In summary, we have developed a practical reaction pro-
tocol for the first direct regioselective allylation of histi-
dine derivatives. The reaction is highly atom-efficient and
affords facile access to N(τ)-allylhistidine derivatives in
excellent yield and purity and without compromising the
optical purity. Furthermore it was demonstrated that the
scope of the reaction could be expanded to other alkyl ha-
lides.
9
H), 2.78 (d, J = 6.5 Hz, 2 H), 3.53 (s, 3 H), 4.21 (q, J = 7.3
Hz, 1 H), 5.13 (s, 2 H), 6.88 (s, 1 H), 7.12 (d, J = 8.0 Hz, 1
H), 7.21 (d, J = 7.5 Hz, 2 H), 7.25–7.37 (m, 3 H), 7.67 (s, 1
H). C NMR (150 MHz, DMSO-d ): δ (major rotamer) =
1
3
6
2
1
3
8.1, 29.7, 49.4, 51.6, 53.7, 78.2, 116.8, 127.3, 127.6, 128.6,
+
37.1, 137.3, 137.8, 155.2, 172.5. MS (ES ): m/e calcd:
60.19 [M + H]; found: 360.24 [M + H].
(
6) N(α)-Boc-N(τ)-propylhistidine Methyl Ester
1
H NMR (400 MHz, DMSO-d ): δ (major rotamer) = 0.78 (t,
6
J = 7.4 Hz, 3 H), 1.34 (s, 9 H), 1.66 (sext, J = 7.1 Hz, 2 H),
2
.79 (d, J = 6.5 Hz, 2 H), 3.57 (s, 3 H), 3.83 (t, J = 6.5 Hz, 2
Acknowledgment
H), 4.22 (q, J = 6.9 Hz, 1 H), 6.87 (s, 1 H), 7.09 (d, J = 8.0
Hz, 1 H), 7.51 (s. 1 H). C NMR (150 MHz, DMSO-d ): δ
13
6
Thanks are expressed to Nathalie Rosenbaum for performing prac-
tical laboratory work and Ute Messinger for the NMR studies.
(major rotamer) = 10.7, 23.8, 28.1, 29.7, 47.5, 51.6, 53.8,
+
7
3
8.2, 116.5, 136.8, 136.9, 155.2, 172.5. MS (ES ): m/e calcd:
12.19 [M + H]; found: 312.23 [M + H].
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
n
ungIifoop
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t
©
Georg Thieme Verlag Stuttgart · New York
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