Chemoselective N-alkylation of Di-N,O-protected tyrosine through specific oxy-anion solvation by non-hydrogen bonding donor solvents

Article abstract of DOI:10.1055/s-2006-932494

N-(2-Nitro-benzenesulfonyl) activated L-tyrosine methyl ester has been directly N-alkylated under solid-liquid phase-transfer catalysis (SL-PTC) conditions and in a coordinating non-hydrogen bonding donor (non-HBD) solvent, which reduces through specific

Full text of DOI:10.1055/s-2006-932494

LETTER
741
Chemoselective N-Alkylation of Di-N,O-protected Tyrosine through Specific
Oxy-Anion Solvation by Non-Hydrogen Bonding Donor Solvents
a
b
b
b
b
N
M
-Alkylation of Protec
i
ted Ty
c
a
CNR – Istituto di Scienze e Tecnologie Molecolari (ISTM), via Golgi 19, 20133 Milano, Italy
Fax +39(02)50314159; E-mail: michele.penso@istm.cnr.it
b
Dipartimento di Chimica Organica e Industriale, Università, via Venezian 21, 20133 Milano, Italy
Received 26 September 2005
(
Scheme 1), and the corresponding N-alkyl-a-nosylamido
Abstract: N-(2-Nitro-benzenesulfonyl) activated L-tyrosine methyl
ester has been directly N-alkylated under solid–liquid phase-trans-
fer catalysis (SL-PTC) conditions and in a coordinating non-hydro-
esters 3 were obtained in excellent yields (80–96%). The
alkylation reactions of a-nosylamido-b-hydroxy esters 4
3
gen bonding donor (non-HBD) solvent, which reduces through (Scheme 1), derived from serine (R = H) and threonine
3
specific solvation the nucleophilicity of the oxy-anionic center of (R = Me), were less chemoselective. In fact, the aliphatic
the N,O-dianion formed by action of an anhydrous inorganic car-
bonate.
hydroxy group under these conditions competes with the
nosylamide for the nucleophilic attack, and significant
Key words: solvent effects, chemoselectivity, alkylations, amino amounts of the corresponding substituted a-nosylamido
acids, phase-transfer catalysis
acrylic esters 7 were formed by 1,2-elimination of an
alcohol unit (R OH) from the unstable di-N,O-alkylated
2
intermediates 6. The substitution of DMF for acetonitrile
Mono-N-alkylated a-amino acid derivatives are a class of improved the N-alkylation chemoselectivity of com-
exciting products, both as pharmacologically active pounds 4, and products 5 were isolated in good yields
compounds and as starting materials for the construction (76–86%).5
1
2
of peptidomimetics. Among the N-alkyl-a-amino acids
In view of these results, we guessed that the alkylation re-
3
preparations, Fukuyama’s amine protocol stands out for
actions of sulfonamido esters derived from a-amino acids
its mild reaction conditions, simplicity and broad range of
5
6
containing a phenol unit (10 –10 times more acidic than
an aliphatic OH) in their side chain would be knottier. In
4
5
applications. Bowman and Coghlan utilized this proce-
dure for the N-alkylation–deprotection of a limited
number of 2-(2-nitro-benzenesulfonylamino) carboxylic
esters, using organic bases under homogeneous con-
fact, due to the close acidity values of the aromatic hy-
droxy group and of the nosylamido group (pk ca. 10–11,
relative to water), the simultaneous deprotonation of both
8
a
9
6
ditions. In a subsequent paper, we reported that solid–
these functions, and the consequent competition between
the two nucleophilic centers of the formed N,O-dianion,
are expected. With the aim of investigating the behavior
of these compounds in the nucleophilic substitution reac-
tions and producing N-alkyl-tyrosine derivatives, an inter-
esting class of new multifunctionalized molecules, we
have chosen as a model the methyl ester of L-N-(2-nitro-
benzenesulfonyl)tyrosine (9, Scheme 2).
7
liquid phase-transfer catalysis (SL-PTC) permitted re-
markable improvements on both times and yields of the
N-alkylation reactions for a wider series of a-nosylamido
esters (Scheme 1). In particular, esters 1 derived from gly-
cine or amino acids bearing in their side chain either a
1
phenyl or an alkyl group (R = Ph, Alkyl), reacted in a
chemo- and stereoselective fashion with alkyl halides 2
under SL-PTC conditions, using acetonitrile as a solvent
R1
CO2Me
H
R1
CO2Me
i
8
0–96%
N
N
Ns
Ns
R2
3
1
R2
N
R2
OH
OH
2
R O
H
H
CO2Me
H
CO2Me
R2
2
N
R3
Ns
R3
Ns
R3
Ns
–R OH
R3
i
ii
Ns
CO2Me
N
76–86%
N
CO Me
2
7
6
4
5
Scheme 1 N-Alkylation of a-nosylamido esters 1 and 4 under SL-PTC conditions. Reagents and conditions: i) R X (2), K CO3 (anhyd),
2
2
+
–
2
+
–
3
Et BnN Cl
, MeCN, 25–80 °C; ii) R X (2), K CO
, Et BnN Cl
, DMF, 25 °C, R = H, Ns = 2-NO –C H –SO .
3
(cat.)
2
3 (anhyd)
3
(cat.) 2 6 4 2
SYNLETT 2006, No. 5, pp 0741–0744
1
7.
0
3.
2
0
0
6
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-932494; Art ID: G29305ST
©
Georg Thieme Verlag Stuttgart · New York

7
42
M. Penso et al.
LETTER
CO2Me
NsNH
CO2Me
NH2
i
85%
HO
HO
9
8
CO2Me
NsNH
ii
CO2Me
CO2Me
RO
RO
1
2
NsN–
NsNR
11
–O
CO2Me
HO
10
NsNR
1
3
2a
2b 2c
2d 2e
2f
2g
2h
2i
CH2Br
MeI EtI
BuI BuBr C8H17I
CH2Br PhCH2Br
2
O N
Cl
NO2
Scheme 2 N-Chemoselective arylsulfonylation–alkylation of methyl tyrosinate. Reagents and conditions: i) NsCl, Na CO3 (lyoph), THF–DMF
2
+
–
(
8:1), 25 °C; ii) RX (2a–i), base, solvent, Q X (cat.).
The nosylamido ester 9 and several arylsulfonamido The reaction of 9 with allyl bromide 2a, in anhydrous ace-
esters of tyrosine were prepared from the corresponding tonitrile (Table 1) and under the PTC conditions applied
a-amino acid esters under SL-PTC conditions without to the nosylamido esters 1 (entries 2 and 3), gave only par-
1
0
protecting the phenolic hydroxy group. As a representa- tial conversion of the substrate and produced a mixture of
tive example (Scheme 2), the methyl tyrosinate 8 was all the possible allylation products 11a–13a, that were
made to react with nosyl chloride, in the presence of lyo- separated and identified. Similar results were obtained by
philized sodium carbonate, by using a THF–DMF mixture operating in THF–DMF and MeCN–DMF mixtures (en-
as solvent. The highest chemoselectivity of N-arylsulfo- tries 4–6). Complete conversion of 9 and an interesting N-
nylation and sulfonamido ester 9 yield were reached in the chemoselectivity were reached in anhydrous DMF at
presence of a small amount of DMF (2.6 mol/mol of sub- 30 °C (entry 7) and 11a was isolated in 60% yield, where-
strate), because this highly ion-coordinating solvent pref- as at 80 °C the di-N,O-substituted 13a (entry 8) was the
erentially solvates the [phenoxide/sodium] ion pairs and major product. Substituting lyophilized sodium carbonate
decreases the charge and hence the nucleophilicity of the for potassium carbonate, even if the reaction times are
oxy-anion.
longer, resulted in higher N-chemoselectivity (79%, entry
), while Cs CO was ineffective also at 30 °C (entry 11)
9
2
3
and large amounts of 12a and 13a were produced.
Table 1 N-Alkylation of 9 with Allyl Bromide 2a under SL-PTC Conditionsa
Entry
Solvent
Base
Temp (°C)
Time (h)
Isolated yields (%)
9
11a
11
38
22
36
35
35
60
20
66
53
34
12a
10
13
21
15
18
17
25
38
–
13a
9
1
2
3
4
5
6
7
8
9
THF
K CO
80
30
80
30
30
30
30
80
30
50
30
120
144
4
63
22
35
18
35
30
–
2
3 anhyd
3 anhyd
3 anhyd
3 anhyd
3 anhyd
3 anhyd
3 anhyd
3 anhyd
MeCN
K CO
27
22
24
12
18
15
42
18
35
48
2
MeCN
K CO
2
THF–DMF (8:1)
THF–DMF (1:2)
MeCN–DMF (1:2)
DMF
K CO
120
54
54
54
4
2
K CO
2
K CO
2
K CO
2
DMF
K CO
–
2
b
DMF
Na CO
96
76
54
15
–
2
3 lyoph
3 lyoph
1
0
1
DMF
Na CO
–
2
1
DMF
Cs CO
–
18
2
3 anhyd
a
Nosylamido ester 9 (1 mmol), 2a (2 mmol), base (4 mmol), TEBA (0.1 mmol), anhyd solvent (2.5 mL).
Without PTC agent, 26% of 11a was isolated after 120 h.
b
Synlett 2006, No. 5, 741–744 © Thieme Stuttgart · New York

LETTER
N-Alkylation of Protected Tyrosine
743
a
+
–
Lyophilized sodium carbonate, which gave the best re- Table 2 N-Allylation of 9 and Effect of the PTC Agent (Q X ) and
sults in the alkylation of 9, was employed as a base in a se-
of the Non-HBD Solvent
ries of reactions carried out in DMF or dimethylacetamide
+
–b
Entry Solvent
Q X
Time
h)
Yield of 11a C
(
DMA) by changing the PTC agent (Table 2). Under these
(%)c
(%)d
(
conditions, the lipophilic tetrabutylammonium salts (en-
tries 2 and 5) were more efficient than TEBA (entry 1) or
than a tetraalkylphosphonium salt (entry 3). In particular,
good yields of 11a and selectivities (≥88%) were obtained
with tetrabutylammonium hydrogensulfate in both DMA
and DMF (entries 4 and 5). The screening of several
aprotic dipolar solvents (entries 4–8), in the presence of
1
2
3
4
5
6
7
DMAe
DMA
DMA
DMF
TEBA
TBAB
54
25
54
37
25
6
70
84
68
75
90
98
93
91
82
96
80
88
95
98
93
91
C H
33P+Bu Br–
16 3
TBA–HSO4
TBA–HSO4
TBA–HSO4
TBA–HSO4
TBA–HSO4
catalytic amounts of TBA–HSO indicated that the best
DMA
DMSO
DMPU
NMP
4
results were reached in DMSO (entry 6), which permitted
also a simple and rapid separation of the product by aque-
1
1
ous workup. The use of N,N¢-dimethylpropylene urea
13
13
(DMPU, entry 7) or N-methyl-pyrrolidin-2-one (NMP,
8
entry 8) as solvents gave good yields in acceptable reac-
tion times but, conversely, these solvents generated more
problems in the workup step than DMSO, due to their philized Na
higher solubility in organic media. The effect of non-HBD
solvents on the alkylation of 9 with a series of activated
and non-activated alkyl halides 2b–i was also investigated
and the best results are reported in Table 3. The activated
alkylating agents 2a,b,g–i gave very good yields (80–
a
Nosylamido ester 9 (1 mmol), allyl bromide (2a, 2 mmol), lyo-
+
–
CO
(4 mmol), Q X (0.1 mmol), anhyd solvent (2.5 mL),
2
3
3
0 °C.
b
TEBA: triethylbenzylammonium chloride; TBA–HSO : tetrabuty-
4
lammonium hydrogensulfate; TBAB: tetrabutylammonium bromide.
c
Isolated yields.
d
e
C: chemoselectivity expressed as: 100 × (mol 11a)/(mol reacted 9).
In DMF 66% of 11a was isolated (see entry 9 of Table 1).
9
8%) under mild reaction conditions, whereas, as expect-
ed, the less activated 2c–f required more drastic condi-
tions, i.e. a higher temperature and longer reaction times.
In general, dimethylsulfoxide was found to be the solvent
of choice for these alkylations, with the exception of butyl
and benzyl bromide (entries 5 and 8) that prefer less polar
non-HBD solvents, such as DMPU and DMA.
In conclusion, methyl L-N-(2-nitro-benzenelsulfonyl)ty- al of the nosyl protecting group.3 This straightforward
rosinate (9) has been chemoselectively N-alkylated under synthetic protocol can be favorably applied to the prepa-
SL-PTC conditions, without protecting the phenolic hy- ration of a new class of multifunctionalized a-amino acid
droxy group through deprotonation to the corresponding derivatives containing, besides an alkylated amino group,
N,O-dianion in the presence of a non-HBD solvent, which a free phenolic unit that is a site for further modifications
of the molecule backbone.
dissociates the ion pairs and specifically solvates the oxy-
anion, decreasing its nucleophility. This alkylation
reactions proceed without racemization of the stereogenic
carbon atom and the N-alkylated derivatives 11 produced
are easily transformed into the enantiomerically pure N-
12
alkyl a-amino esters (or acids) by simple and mild remov-
–5
Table 3 N-Alkylation of 9 Using a Series of Alkylating Agents RX under SL-PTC Conditionsa
20
Entry RX
Solvent
DMSO
DMSO
DMSO
DMSO
DMPU
DMSO
DMSO
DMA
Temp (°C) Time (h) Product
Yield (%)b ee (%)c
[a]D
c
1
2
3
4
5
6
7
8
9
CH =CH–CH Br
2a
2b
2c
2d
2e
2f
30
30
50
50
50
50
30
30
50
6
11a
11b
11c
11d
11e
11f
11g
11h
11i
98
98
86
74
64
68
86
96
80
100 (A)
100 (A)
100 (B)
92 (B)
69(B)
–23.6
0.83
0.60
0.84
1.00
1.00
1.00
0.79
0.90
0.56
2
2
MeI
1
+101.5
–17.7
–21.0
–15.7
–24.2
–58.7
–32.1
–98.2
EtI
1.5
BuI
22
BuBr
C H I
48
20
8
93 (B)
95 (B)
100 (B)
100d
8
17
HC≡C–CH Br
2g
2h
2i
2
PhCH Br
8
2
2,4-(NO ) C H Cl
DMSO
0.5
2
2
6
3
a
b
c
d
Nosylamido ester 9 (1 mmol), 2 (2 mmol), lyophilized Na CO (4 mmol), TBA–HSO (0.1 mmol), anhyd solvent (2.5 mL).
2
3
4
Isolated yields.
®
®
Determined by HPLC analysis on Daicel columns (A, CHIRALPAK AD; B, CHIRALCEL OD), using i-PrOH–hexane mixtures as eluant.
1
Determined by H NMR analysis, using (R)-(–)-Pirkle shift reagent.
Synlett 2006, No. 5, 741–744 © Thieme Stuttgart · New York

7
44
M. Penso et al.
LETTER
(9) March, J. Advanced Organic Chemistry, 4th ed.; Wiley-
Interscience: New York, 1992, 251.
10) Penso, M.; Albanese, D.; Landini, D.; Lupi, V.; Tricarico, G.
Eur. J. Org. Chem. 2003, 4513.
11) Typical Procedure for the N-Alkylation: Synthesis of
L-N-Allyl-N-(2-nitrophenyl)sulfonyl Tyrosine Methyl
Ester (11a).
Acknowledgment
This work was supported by CNR (Italy) and MIUR (Rome).
(
(
References and Notes
(
(
1) Petrillo, E. W.; Ondetti, M. A. Med. Res. Rev. 1982, 2, 1.
2) (a) Bhatt, U.; Mohamed, N.; Just, G.; Roberts, E.
Tetrahedron Lett. 1997, 38, 3679. (b) Pohlmann, A.;
Schanen, V.; Guillaume, D.; Quirion, J.-C.; Husson, H.-P. J.
Org. Chem. 1997, 62, 1016.
In a dried flask, lyophilized sodium carbonate (424 mg, 4
mmol) was added to a solution of 9 (380 mg, 1 mmol), allyl
bromide (2a, 242 mg, 2 mmol) and tetrabutylammonium
hydrogensulfate (34 mg, 0.1 mmol) in anhyd DMSO (2.5
mL). The heterogeneous mixture was stirred at 30 °C for 6
h, controlling by TLC analysis (EtOAc–hexane, 2:3), then
the crude was diluted with EtOAc (10 mL), washed with an
(3) (a) Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1998, 120,
2
1
1
690. (b) Manavalan, P.; Momany, F. A. Biopolymers 1980,
9, 1943. (c) Dorow, R. L.; Gingrich, D. E. J. Org. Chem.
995, 60, 4986; and references therein. (d) Cheung, S. T.;
Benoiton, N. L. Can. J. Chem. 1977, 55, 906. (e) Rich, D.
H.; Tam, J.; Mathiaparanam, P.; Grant, J. Synthesis 1975,
aq sat. solution of NH Cl (2.5 mL), then with brine (2 × 5
4
mL). The aqueous phases were extracted with EtOAc (5 × 5
mL); the organic phases were collected and washed with
H O (5 mL), brine (2 × 5 mL) and dried over MgSO . The
4
02.
4) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
995, 36, 6373. (b) Kan, T.; Kobayashi, H.; Fukuyama, T.
2
4
solvent was distilled under vacuum and the residue was
purified by flash chromatography (EtOAc–hexane, 2:3).
(
1
N-Allyl derivative 11a, pale yellow oil (412 mg, 98%); ee
Synlett 2002, 1338. (c) Kan, T.; Kobayashi, H.; Fukuyama,
T. Synlett 2002, 697. (d) Fukuyama, T.; Cheung, M.; Jow,
C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831;
and references therein.
®
1
00% [HPLC: column CHIRALPAK AD (Daicel); 25 °C;
i-PrOH–hexane (15:85); flow 0.8 mL/min; l = 266.8 nm; t
R
2
0
1
2
7.575 min]; [a]D –23.6 (c 0.83, CHCl ). H NMR
3
(
CDCl ): d = 7.84 (d, 1 H, J = 7.6 Hz), 7.64 (d, 1 H, J = 7.6
(
(
(
5) Bowman, W. R.; Coghlan, D. R. Tetrahedron 1997, 53,
3
Hz), 7.58–7.54 (m, 2 H), 7.07 (d, 2 H, J = 8.1 Hz), 6.68 (d, 2
H, J = 8.4 Hz), 5.85–5.71 (m, 1 H), 5.35 (br s, 1 H), 5.20 (dd,
1
5787.
6) Albanese, D.; Landini, D.; Lupi, V.; Penso, M. Eur. J. Org.
Chem. 2000, 1443.
7) For monographs and reviews see inter alia: (a) Montanari,
F.; Landini, D.; Rolla, F. Top. Curr. Chem. 1982, 101, 147.
1
H, J = 17.3, 1.3 Hz), 5.11 (dd, 1 H, J = 9.9, 1.8 Hz), 4.85
(
t, 1 H, J = 7.4 Hz), 4.13–3.98 (m, 2 H), 3.56 (s, 3 H), 3.27
(
dd, 1 H, J = 14.3, 7.7 Hz), 2.96 (dd, 1 H, J = 14.3, 7.6 Hz).
1
3
C NMR-APT (CDCl ): d = 170.8 (CO), 154.7 (COH),
(
(
b) Makosza, M.; Fedorynki, M. Adv. Catal. 1988, 35, 375.
c) Dehmlow, E. V.; Dehmlow, S. Phase-Transfer Catalysis;
VCH: Weinheim, 1993. (d) Starks, C. M.; Liotta, C.;
Halpern, M. Phase-Transfer Catalysis. Fundamentals,
Applications and Industrial Perspectives; Chapman and
Hall: New York, 1994.
3
1
48.0 (CNO ), 134.2 (CH=), 133.6 (CH), 133.2 (CSO ),
2
2
1
31.6 (CH), 131.0 (CH), 130.4 (2 CH), 128.0 (C ), 124.0
Ph
(
(
CH), 118.5 (CH =), 115.4 (2 CH), 61.4 (CH-N), 52.2
2
OCH ), 48.8 (CH N), 35.5 (CH Ph). Anal. Calcd for
3
2
2
C H N O S (420.44): C, 54.28; H, 4.79; N, 6.66. Found: C,
19 20
2
7
54.37; H, 4.76; N, 6.69.
(
8) Nyasse, B.; Grehn, L.; Ragnarsson, U.; Maia, H. L. S.;
Monteiro, L. S.; Leito, I.; Koppel, I.; Koppel, J. J. Chem.
Soc., Perkin Trans. 1 1995, 2025.
(
12) Reichardt, C. Solvents and Solvent Effects in Organic
Chemistry; Wiley-VCH: Weinheim, 2003, 246–250.
Synlett 2006, No. 5, 741–744 © Thieme Stuttgart · New York