A convenient transformation of α-alkylserines into α-halogenomethyl-α-alkylglycines

Article abstract of DOI:10.1016/j.tetlet.2008.08.098

An efficient and facile synthesis of N-Boc-α-chloromethyl- and α-bromomethyl-α-alkylglycines is reported that involves cyclization of N-Boc-α-alkylserines to the corresponding β-lactones under Mitsunobu reaction conditions, followed by ring opening with anhydrous MgCl₂ or MgBr₂.

Full text of DOI:10.1016/j.tetlet.2008.08.098

Tetrahedron Letters 49 (2008) 6445–6447
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Tetrahedron Letters
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A convenient transformation of a-alkylserines
into
a-halogenomethyl-
a-alkylglycines
*
Adam Kudaj, Aleksandra Olma
_
´
Institute of Organic Chemistry, Technical University, 90-924 Łódz, Zeromskiego 116, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 July 2008
Revised 18 August 2008
Accepted 27 August 2008
Available online 31 August 2008
An efficient and facile synthesis of N-Boc-
a
-chloromethyl- and
-alkylserines to the corresponding b-lactones under Mitsun-
obu reaction conditions, followed by ring opening with anhydrous MgCl2 or MgBr2.
Ó 2008 Elsevier Ltd. All rights reserved.
a-bromomethyl-a-alkylglycines is
reported that involves cyclization of N-Boc-
a
Keywords:
N-Boc-
N-Boc-
N-Boc-
a
a
a
-chloromethyl-
-bromomethyl-
-alkylserine b-lactones
a
a
-alkylglycines
-alkylglycines
a,a-Disubstituted glycines
Mitsunobu reaction
1. Introduction
involving the synthesis of the racemic a-hydroxymethyl analogue
of various amino acids7 and their resolution by fractional crystalli-
zation of appropriate diastereoisomeric salts. The absolute config-
a,a-Disubstituted glycines have been used widely in medicinal
chemistry and biochemistry to restrict the flexibility of peptides
and to enhance their potency and their resistance toward enzy-
matic hydrolyses.1 Incorporation of this moiety into biologically
active peptides might become a powerful method for the design
uration of some
chemical correlation with the relevant
X-ray analysis.8
-Alkylserines could also be obtained via the dia-
a
-hydroxymethylamino acids was determined by
a-methylamino acids or by
a
stereoselective alkylation of pyramidalized bicyclic serine enolates
of peptidomimetic therapeutics. Moreover the
a,a-disubstituted
(bicyclic N,O-acetals derived from serine).9 The ease with which
glycines are often found in nature either in the free form or as
a
-hydroxymethyl-
amino acids encouraged us to explore the possibility of utilizing
these derivatives as starting materials for the synthesis of -halog-
enomethyl- -amino acids. Our attempts to transform the hydroxy-
a-amino acids can be prepared from the parent
constituents of biologically active natural products.2 The biological
significance and synthetic utility of
a
,a-disubstituted glycines
a
continue to stimulate the development of new routes to these
compounds. Our research has focused on the synthesis of con-
a
methyl group into a chloromethyl group using the standard
conditions for the transformation of serine into chloromethylala-
nine10 failed. The low reactivity of the hydroxyl group may be ex-
plained by its location being similar to the neopentyl position.
Herein, we present the use of N-Boc-
the preparation of N-protected -halogenomethyl-
acids. Only a few synthetic strategies directed toward the synthesis
of the selected -halogenomethylamino acids have been de-
scribed.11–14 Bey et al.11 obtained various racemic
-halogeno-
strained amino acid building blocks,
a-alkylserines, and their
incorporation into biologically active peptidomimetics.3 Recently,
we reported the synthesis of optically pure N-protected and free
3-amino-3-alkyl-2-oxetanones from
a
-alkylserines.4 These b-lac-
a
-alkylserine b-lactones for
tones are excellent starting materials for further derivatization in
medicinal chemistry. The ring opening of alkylserine lactones with
a
a-alkylamino
sulfur nucleophiles resulted in S-protected N-Boc-
ines.5 The use of sodium azide as a nucleophile provides N-
Boc- -alkyl-b-azidoalanines, which can be readily reduced to the
corresponding N-Boc-
-alkyl-b-aminoalanines.6 The optically
active N-Boc- -alkylserines, used as starting materials, are easily
a
-alkylcyste-
a
a
a
methylamino acids in the regioselective alkylation of a Schiff
a
base ester of amino acids with halomethanes. Han and Frey12 syn-
a
thesized N-benzylidene-
D
,L-
a-bromomethylalanine ethyl ester by
available following the procedure developed in our laboratory,
the alkylation reaction of N-benzylidene-D,L
-alanine ethyl ester
with CH2Br2 in the presence of potassium tert-butoxide and 18-
crown-6. Furthermore, Kedrowski and Heathcock have described
the synthesis of ZNHC(CH3)(CH2X)COOMe (X = Cl, I) by alkylation
* Corresponding author. Tel.: +48 426313144; fax: +48 426365530.
E-mail address: aleksandra.olma@p.lodz.pl (A. Olma).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.098

6446
A. Kudaj, A. Olma / Tetrahedron Letters 49 (2008) 6445–6447
R
R
R
O
Ph P, DEAD
3
Boc O, KOH
2
H2N
COOH
BocHN
COOH
CH2OH
BocHN
Et N/MeOH
3
AcOEt
CH2OH
O
1
2
3
R
MgCl
2
BocHN
COOH
COOH
CH2Cl
4
R
MgBr
2
BocHN
CH2Br
5
R=CH3 (a), CH2CH(CH3)2 (b), CH(CH3)2 (c), CH2C6H5 (d)
Scheme 1. Synthesis of a-chloromethyl-4 and a-bromomethyl-a-alkylglycines 5.
of 2-aryl-3-carbobenzyloxy oxazolidinones with ICH2X.13 Bucha-
of compounds 2 was accomplished by comparison of the obtained
nan et al. obtained racemic
c
-fluoroglutamic acid via two indepen-
data with those previously described by us.3
dent methods, both of which involved a Michael reaction.14
Scheme 1 outlines our method for the synthesis of N-protected
3. General procedure for the preparation N-Boc-a-alkylserine-
a
-chloromethyl- and
The starting N-Boc-
potassium salt of -alkylserines 1 and Boc2O in boiling methanol in
a
a
-bromomethyl-
-alkylserines 2 were synthesized from the
a-alkylamino acids.
b-lactones 3
a
To a solution of triphenylphosphine (866 mg, 3.3 mmol) in dry
the presence of triethylamine as a base. Using these reaction con-
ditions, we were able to obtain products 2 in high yields (79–84%)
ethyl acetate (6 ml), DEAD (3.3 mmol) was added at ꢁ10 °C. The
mixture was stirred for 15 min, and then N-Boc-a-alkylserine
after 3–4 h. The standard procedure for the synthesis of N-Boc-a-
(3 mmol) was added. Stirring was continued for 1.5 h at ꢁ10 °C
and then for 1.5 h at room temperature. The mixture was diluted
with n-hexane (6 ml) and allowed to stand in a refrigerator for
2 h. The solid N,N0-diethoxycarbonylhydrazine and triphenylphos-
phine oxide were removed by filtration. The filtrate was concen-
trated in vacuo, and the oily residue was purified by flash
chromatography on silica gel 60 (43–60 mesh) using ethyl ace-
alkylserines usually takes two to three days.3 We optimized the
conditions for the synthesis of 3, using anhydrous ethyl acetate
instead of THF. Most of the side products (mainly N,N0-diet-
hoxycarbonylhydrazine) could be removed by filtration, which
significantly simplified the purification procedure. The ring
opening of N-Boc-
chloride resulted in the formation N-Boc-
glycines in 86–91% yields. The use of magnesium bromide
provided N-Boc- -bromomethyl- -alkylglycines in 95–99% yields.
a-alkylserine lactones
3
with magnesium
a
-chloromethyl- -alky-
a
tate-n-hexane (1:3 and then 1:1) as eluent. The N-Boc-a-alkylser-
ine-b-lactones were obtained in 74–85% yields. Compounds 3a–d
were characterized on the basis of 1H NMR data.15 The spectral
data of compound 3d are the same as those described by Broadrup
et al.16
a
a
2. General procedure for the preparation N-Boc-a-
hydroxymethylamino acids 2
4. General procedure for the preparation of N-Boc-(S)-
a-
A mixture of
a-hydroxymethylamino acid 1 (20 mmol), KOH
chloromethyl 4 and N-Boc-(S)- -bromomethyl- -alkylglycines
a
a
(1.12 g, 20 mmol), Et3N (5.56 ml, 40 mmol), and methanol (40–
60 ml) was stirred and heated under reflux, to afford a homo-
genous solution, and then Boc2O (6.54 g, 30 mmol) dissolved in
MeOH (5 ml) was added. The reaction mixture was stirred under
reflux for 90 min, and an additional amount of Boc2O (2.18 g,
10 mmol) was added. After 30 min stirring and heating, the reac-
tion was continued at room temperature for another 90 min after
which the methanol was evaporated. The residue was dissolved
in water and extracted with diethyl ether (2 ꢀ 10 ml). The aqueous
layer was cooled to 5–10 °C, acidified to pH 2–3 with 1 N NaHSO4,
saturated with NaCl, and extracted with EtOAc (3 ꢀ 50 ml). The
combined organic layers were washed with brine, dried over anhy-
drous MgSO4, and concentrated under reduced pressure. The
resulting colorless oil was crystallized from AcOEt/n-hexane (v/v
5, ((S)-2-alkyl-2-N-(tert-butoxycarbonyl)amino-3-
halogenopropionic acids)
Anhydrous MgCl2 or MgBr2 (2 mmol) was suspended in dry THF
and sonicated for 10 min, and then N-Boc-a-alkylserine-b-lactone
3 (1 mmol) was added as a solid. The mixture was stirred for 15–
90 min (TLC). The solvent was removed in vacuo at 35 °C, and
the residue was dissolved in water, washed with diethyl ether
(2 ꢀ 10 ml), acidified to pH 2–3 with 1 N NaHSO4, and extracted
with AcOEt (3 ꢀ 10 ml). The combined organic phases were
washed with brine, dried over anhydrous MgSO4, and concentrated
in vacuo at 35–40 °C. The crude material (colorless oil or white
crystals, yields 83–99%) was chromatographically pure. All new
compounds were characterized on the basis of 1H and 13C NMR
data.17,18
1:20) to yield N-Boc-a-alkylserines in 79–84% yields. Identification

A. Kudaj, A. Olma / Tetrahedron Letters 49 (2008) 6445–6447
6447
J = 7,0 Hz, CH), 4,21 (d, J = 5.0 Hz, 1H, CH2), 4,39 (d, J = 5.0 Hz, 1H, CH2), 7.50 (s,
1H, NH), 3c (N-Boc-(S)-3-amino-3-iso-butyl-2-oxetanone) 1H NMR (250 MHz,
DMSO-d6) d 0.84 (d, J = 6.6 Hz, 3H, CH3), 0.88 (d, J = 6.6 Hz, 3H, CH3), 1.36 (s, 9H,
t-Bu), 1.60–1.77 (m, 2H, CH2), 1.82–1.98 (m, 1H, CH), 4.20 (d, J = 4.6 Hz, 1H,
CH2–O), 4,46 (d, J = 4.6 Hz, 1H, CH2–O), 7.46 (s, 1H, NH).
In conclusion, we have demonstrated the utility of N-Boc-
alkylserine-b-lactones for the efficient synthesis of optically pure
a-
a
C -tetrasubstituted
a-amino acids, a-chloromethyl- and a-bromo-
methyl- -alkylglycines in excellent yields.
a
16. Broadrup, R. L.; Wang, B.; Malachowski, W. P. Tetrahedron 2005, 61, 10277–
10284.
Acknowledgment
17. Characterization data for: Compound 4a (N-Boc-(S)-a-chloromethylalanine)
yield 93%; white crystals: mp 109–110 °C (dec); IR (KBr) 727 cmꢁ1; ½a D20
ꢂ
49.4 (c
1, CHCl3); 1H NMR (250 MHz, CDCl3) d 1.45 (s, 9H, t-Bu), 1.57 (s, 3H, CH3), 4.01–
4.06 (m, 2H, CH2), 13C NMR (75 MHz, CDCl3) d 22.0, 28.2, 47.2, 60.0, 80.5, 154.0,
176.8; MS (FAB) m/z 238.1 (M+1); calcd for C6H16O4NCl 237.7; Compound 4b
This work was supported by the Ministry of Science and Higher
Education (Grant No. 204 041 32/0879).
(N-Boc-(S)-a-chloromethylleucine) yield 91%; white crystals: mp 138–139 °C
(dec); IR (KBr) 727 cmꢁ1; ½a D20
ꢂ
12.6 (c 1, CHCl3); 1H NMR (250 MHz, CDCl3) d
References and notes
0.88 (d, J = 6.3 Hz, 3H, CH3), 0.97 (d, J = 6.3 Hz, 3H, CH3), 1,45 (s, 9H, t-Bu), 1.60–
1.77 (m, 2H, CH2), 2.24–2.33 (m, 1H, CH), 3.81 (d, J = 10.0 Hz, 1H, CH2–Cl), 4.37
(d, J = 10.0 Hz, 1H, CH2–Cl), 5.63 (s, 1H, NH), 13C NMR (75 MHz, CDCl3) d 23.0,
23.4; 24.7, 28.2, 41.5, 46.7, 64.1, 80.1, 153.9, 176.5; MS (FAB) m/z 280.3 (M+1);
1. Cativiela, C.; Dìaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2007, 18, 569–
623.
2. For example, see: Burgess, A. W.; Leach, S. Biopolymers 1973, 12, 2691–2712;
Seebech, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef, R. Helv. Chim. Acta 1987, 70,
1194–1216.
3. For example, see: Metzger, J.; Olma, A.; Leplawy, M. T.; Jung, G. Z. Naturforsch.
1987, 42b, 1195–1201; Olma, A.; Misicka, A.; Tourwe, D.; Lipkowski, A. W. Lett.
Pept. Sci. 1998, 5, 383–385; Łempicka, E.; Slaninowa, J.; Olma, A.; Lammek, B. J.
Pept. Sci. 1999, 53, 554–559; Olma, A.; Gniadzik, A.; Lipkowski, A. W.; Łachwa,
M. Acta Biochem. Pol. 2001, 48, 1165–1168; Olma, A.; Tourwe, D. Lett. Pept. Sci.
2000, 7, 93–96; Olma, A.; Lipkowski, A. W.; Łachwa, M. J. Pept. Res. 2003, 61,
45–52; Zabłotna, E.; Kret, A.; Jas´kieiwcz, A.; Olma, A.; Leplawy, M. T.; Rolka, K.
Biochem. Biophys. Res. Commun. 2006, 340, 823–828.
calcd for C12H22O4NCl 279.8; Compound 4c (N-Boc-(S)-
a
-chloromethylvaline)
yield 86%; white crystals: mp 146–147 °C (dec); IR (KBr) 727 cmꢁ1 a 2D0
½ ꢂ
ꢁ2.8 (c
1, CHCl3); 1H NMR (250 MHz, CDCl3) d 1.07 (d, J = 7.0 Hz, 6H, (CH3)2), 1.50 (s,
9H, t-Bu), 2.47–2.63 (m, 1H, CH), 4.20 (d, J = 10.5 Hz, 1H, CH2), 4.60 (d,
J = 10.5 Hz, 1H, CH2), 5.51 (s, 1H, NH), 13C NMR (75 MHz, CDCl3) d 17.2, 17.8,
28.2, 32.7, 45.2, 67.3, 80.0, 155.0, 174.6; MS (FAB) m/z 266.2 (M+1); calcd for
C
11H20O4NCl 265.7; Compound 4d (N-Boc-(S)-
a
-chloromethylphenylalanine)
yield 95%; colorless oil; IR (KBr) 727 cmꢁ1; ½a D20
ꢂ
ꢁ42.1 (c 1, CHCl3); 1H NMR
(250 MHz, CDCl3) d 1.45 (s, 9H, t-Bu), 3.15 (d, J = 13.5 Hz, 1H, CH2–Ph), 3.60 (d,
J = 13.5 Hz, 1H, CH2–Ph), 4.03 (d, J = 12.0 Hz, 1H, CH2Cl), 4.54 (d, J = 12.0 Hz, 1H,
CH2–Cl), 5.53 (s, 1H, NH), 7.18–7.33 (m, 5H, C6H5), 13C NMR (75 MHz, CDCl3) d
28.3, 30.5, 38.9, 45.9, 65.6, 80.2, 127.3, 128.4, 129.8, 134.7, 154.2, 174.5; MS
(FAB) m/z 314.1 (M+1); calcd for C15H20O4NCl 313.8;.
4. Olma, A.; Kudaj, A. Tetrahedron Lett. 2005, 46, 6239–6249.
5. Olma, A. Pol. J. Chem. 2004, 78, 831–835.
6. Kudaj, A.; Olma, A. Tetrahedron Lett. 2007, 48, 6794–6797.
18. Characterization data for 5a (N-Boc-(S)-
a
-bromomethylalanine): yield 99%;
´
7. Kaminski, Z. J.; Leplawy, M. T.; Zabrocki, J. Synthesis 1973, 792–793.
colorless oil; IR (KBr) 533 cmꢁ1; ½a D20
ꢂ
10.69 (c 1, CHCl3); 1H NMR (250 MHz,
8. Leplawy, M. T.; Olma, A. Pol. J. Chem. 1979, 53, 354–357; Olma, A. Pol. J. Chem.
CDCl3) d 1.46 (s, 9H, t-Bu), 1.66 (s, 3H, CH3), 3.94–3.98 (m, 2H, CH2), 5.41 (s, 1H,
NH), 13C NMR (75 MHz, CDCl3) d 22.8, 28.2, 36.8, 59.5, 80.2, 154.4, 176.2; MS
_
1996, 70, 1442–1447; Wieczorek, W.; Bukowska-Strzyzewska, M.; Leplawy, M.
T.; Olma, A. J. Crystallogr. Spectrosc. Res. 1989, 19, 257–265; Wieczorek, W.;
(FAB) m/z 282.0; calcd for C9H16O4NBr 282.1; 5b (N-Boc-(S)-a-
_
Bukowska-Strzyzewska, M.; Leplawy, M. T.; Olma, A. J. Crystallogr. Spectrosc.
bromomethyloleucine): yield 99%; white crystals: mp 112–113 °C (dec); IR
_
Res. 1991, 21, 209–215; Wieczorek, W.; Bukowska-Strzyzewska, M.; Olma, A.;
(KBr) 533 cmꢁ1; ½a D20
ꢂ
9.37 (c 1, CHCl3); 1H NMR (250 MHz, CDCl3) d 0.88 (d,
Kamin´ ski, Z. J.; Leplawy, M. T. J. Crystallogr. Spectrosc. Res. 1991, 21, 107–112;
Witkowska, R.; Kaczmarek, K.; Crisma, M.; Toniolo, C.; Zabrocki, J. J. Pept. Sci.
2001, 7, 619–625.
J = 6.3 Hz, 3H, CH3), 0.94 (d, J = 6.3 Hz, 3H, CH3), 1.46 (s, 9H, t-Bu), 1.62–1.82
(m, 2H, CH2), 2.25–2.41 (m, 1H, CH), 3.69 (d, J = 10.1 Hz, 1H CH2–Br), 4.32 (d,
J = 10.1 Hz, 1H, CH2–Br), 5,75 (s, 1H, NH), 13C NMR (75 MHz, CDCl3) d 21.7, 21.8,
23.5, 26.5, 34.4, 40.4, 61.9, 78.3, 152.1, 174.5; MS (FAB) m/z; 324.1 calcd for
9. Jimenez-Oses, G.; Aydillo, C.; Busto, J. H.; Zurbano, M. M.; Peregrina, J.;
Avenoza, A. J .Org. Chem. 2007, 72, 5399–5402.
10. Fischer, E.; Raske, K. Ber 1907, 40, 3717–3724.
11. Bey, P.; Vevert, J.-P.; Van Dorsselaer, V.; Kolb, M. J. Org. Chem. 1979, 44, 2732–
2742.
C
12H22O4NBr 324.2; 5c (N-Boc-(S)-
a
-bromomethylvaline): yield 95%; colorless
oil; IR (KBr) 533 cmꢁ1; ½a D20
ꢂ
6.66 (c 1, CHCl3); 1H NMR (250 MHz, CDCl3) d 1.04
(d, J = 7.0 Hz, 6H, (CH3)2CH), 1.46 (s, 9H, t-Bu), 2.34–2.63 (m, 1H, CH), 4.06 (d,
J = 10.1 Hz, 1H, CH2), 4.40 (d, J = 10.1 Hz, 1H, CH2), 5.51 (s, 1H, NH), 13C NMR
(75 MHz, CDCl3) d 17.5, 18.1, 28.3, 33.5, 35.1, 66.9, 80.1, 154.2, 174.3; MS (FAB)
12. Han, O.; Frey, P. A. J. Am. Chem. Soc. 1990, 112, 8982–8983.
13. Kedrowski, B. L.; Heathcock, C. H. Heterocycles 2002, 58, 601–634.
14. Buchanann, R. L.; Dean, F. H.; Pattison, F. L. M. Can. J. Chem. 1962, 40, 1571–
1575.
m/z 310.2; calcd for
C11H20O4NBr 310.2; Compound 5d (N-Boc-(S)-a-
bromomethylphenylalanine): yield 91%; colorless oil; IR (KBr) 533 cm-1; ½a D20
ꢂ
ꢁ43.21 (c 1, CHCl3); 1H NMR (250 MHz, CDCl3) d 1.49 (s, 9H, t-Bu); 3.14 (d,
J = 13.0 Hz, 1H,CH2–Ph), 3.61 (d, J = 13.0 Hz, 1H, CH2–Ph), 3.89 (d, J = 10.5 Hz,
1H, CH2–Br), 4.39 (d, J = 10.5 Hz, 1H, CH2–Br), 5.44 (s, 1H, NH), 7.10–7.30 (m,
5H, C6H5); 13C NMR (75 MHz, CDCl3) d 28.3, 35.2, 39.6, 65.2, 80.3, 127.3. 128.4,
129.7, 135.0, 154.1, 174.6; MS (FAB) m/z 358.1; calcd for C15H20O4NBr 358.2.
15. Spectral data: Compound 3a (N-Boc-(S)-3-amino-3-methyl-2-oxetanone) 1H
NMR (250 MHz, DMSO-d6) d 1.37 (s, 9H, t-Bu), 1.41 (s, 3H, CH3) 4.11 (d,
J = 4.5 Hz, 1H, CH2), 4.45 (d, J = 4.5 Hz, 1H, CH2), 7,69 (s, 1H, NH) 3b (N-Boc-(S)-
3-amino-3-iso-propyl-2-oxetanone) 1H NMR (250 MHz, DMSO-d6) d 0.94 (d,
J = 7.0 Hz, 3H, CH3), 0.95 (d, J = 7.0 Hz, 3H, CH3), 1.38 (s, 9H, t-Bu), 2.01 (sept,