The synthesis of Fmoc-O-allyl β-serine

Article abstract of DOI:10.1016/j.tetasy.2008.12.022

Two concise routes for the synthesis of the title amino acid have been developed. The first route employs Seebach's general approach [Seebach, D.; Lelais, G.; Micuch, P.; Josien-Lefebvre, D.; Rossi, F. Helv. Chim. Acta 2004, 87, 3131] with Arndt Eistert h

Full text of DOI:10.1016/j.tetasy.2008.12.022

Tetrahedron: Asymmetry 19 (2008) 2861–2863
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The synthesis of Fmoc-O-allyl b-serine
Ylva Bergman a, Marisa Ciampini a, Sania Jalal a, Helen Rachel Lagiakos a,
Marie-Isabel Aguilar b, Patrick Perlmutter a,
*
a School of Chemistry, Monash University, Melbourne Vic 3800, Australia
b Department of Biochemistry and Molecular Biology, Monash University, Melbourne Vic 3800, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Two concise routes for the synthesis of the title amino acid have been developed. The first route employs
Seebach’s general approach [Seebach, D.; Lelais, G.; Micuch, P.; Josien-Lefebvre, D.; Rossi, F. Helv. Chim.
Received 15 October 2008
Accepted 10 December 2008
Available online 24 January 2009
Acta 2004, 87, 3131] with Arndt Eistert homologation of Boc-O-allyl
a-serine as the key process. The sec-
ond route employs an approach using Boc- -aspartic acid as a starting material [Salzmann, T.N.; Ratcliffe,
a
R.W.; Christensen, B.G.; Bouffard, F.A. J. Am. Chem. Soc. 1980, 102, 6163; Rodriguez, M.; Llinares, M.; Dou-
lut, S.; Heitz, A.; Martinez, J. Tetrahedron. Lett. 1991, 32, 923] with a selective palladium-catalysed O-ally-
lation [Haight, A.R; Stoner, E.J.; Peterson, M.J.; Grover, V.K. J. Org. Chem. 2003, 68, 8092] as key processes.
These two routes are evaluated for their relative efficiency and safety.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
provided the new b-amino acid, Boc-O-allyl-b-serine 6, again in
almost quantitative yield. Removal of the Boc group was best ef-
As part of a programme directed towards the synthesis of new
materials based on stapled b-peptides,5 we required b-amino acid,
Fmoc-O-allyl-b-serine 1. This amino acid has not been reported
previously. Of the many approaches to the synthesis of enantiome-
rically pure b-amino acids, those of Seebach1 and Salzmann (in the
fected by employing TFA in DCM. Reprotection with Fmoc–OSu
thus provided the target compound 1 in 62% overall yield from 2.
In order to avoid the use of the hazardous diazomethane, espe-
cially for larger-scale work, we explored the use of TMS-diazo-
methane7 as
a safer alternative. However, yields with this
HO
HO
O
O
O
O
OH
BocHN
BocHN
OBn
FmocHN
OH
O
3
2
1
Figure 1.
context of b-lactams)2 appeared applicable. Each will be discussed
in turn (see Fig. 1).
O
O
(i)
OH
BocHN
N2
2. Results and discussion
BocHN
O
O
5
4
Seebach’s general approach to the synthesis of b-amino acids
involves Arndt Eistert homologation1 of the corresponding
a
-ami-
-amino acid,
-serine 4, was a known compound.6 Treatment of 4
(ii)
no acid (Scheme 1). In our case, the corresponding
Boc-O-allyl-
a
a
O
(iii)
with triethylamine and ethyl chloroformate generated the mixed
anhydride, which was then reacted with diazomethane to give dia-
zoketone 5 in excellent yield. Silver-catalysed rearrangement then
O
1
BocHN
OH
6
Scheme 1. Reagents and conditions: (i) ClCO2Et, Et3N, THF, ꢀ25 °C to rt, o/n (ii)
CF3CO2Ag, Et3N, THF/H2O, ꢀ25 °C to rt, o/n (iii) (a) TFA, DCM, rt, 1 h; (b) Na2CO3,
FmocOSu, acetone, rt, o/n.
* Corresponding author.
E-mail address: patrick.perlmutter@sci.monash.edu.au (P. Perlmutter).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.022

2862
Y. Bergman et al. / Tetrahedron: Asymmetry 19 (2008) 2861–2863
reagent were consistently poor giving, at best, approximately 25%
yields for the conversion of 4 to 5.
was bubbled across to the reaction flask. Once consumption of
diazald was noted, the reaction was allowed to warm to room
temperature and stirred overnight. Excess diazomethane was
quenched by the addition of acetic acid (a few drops) while stir-
ring. The reaction mixture was diluted with diethyl ether, washed
with a saturated aqueous NaHCO3 solution, saturated aqueous
NH4Cl and brine. The organic layer was dried over MgSO4 and con-
centrated in vacuo to give the crude product, which was purified
by flash chromatography (1:1 ethyl acetate:hexanes) to afford 5
(100 mg, 91%) as a colourless oil.
The second route takes advantage of the selective transforma-
tion of the
a-carboxylic acid in partially protected aspartate 3,
yielding alcohol 7 in good yield (Scheme 2).2,3 Initial attempts to
allylate the hydroxyl group with allyl bromide and sodium hydride
gave lactone 98 as the main product. Switching to palladium-cata-
lysed allylation4 with allyl ethyl carbonate somewhat depressed
production of lactone 9 providing the O-allyl product 8 in 42%
isolated yield. Ester hydrolysis then produced 6, which as we have
shown above could be converted into the desired target in two
steps. In principle, hydrolysis of lactone 9 should provide 6; how-
ever, this has yet to be investigated.
4.1.2. Alternative procedure
Boc-
(3 mL) under an atmosphere of nitrogen and was cooled to
ꢀ25 °C. Triethylamine (91 L, 0.65 mmol) and ethyl chloroformate
(63 L, 0.65 mmol) were added dropwise, and the resulting mixture
L-allyl serine 4 (153 mg, 0.62 mmol) was dissolved in THF
l
HO
O
l
O
(i)
O
(ii)
was stirred at this temperature for 1 h. The reaction was allowed to
3
BocHN
OBn
O
BocHN
OBn
warm to 0 °C, and a 2.0 M solution of (trimethylsilyl)-diazomethane
in diethyl ether (620 lL, 1.24 mmol) was added. The resulting yel-
7
8
6
low solution was allowed to warm to room temperature overnight.
The reaction mixture was diluted with diethyl ether, washed with a
saturated aqueous NaHCO3 solution, saturated aqueous NH4Cl and
brine. The organic layer was dried over MgSO4 and concentrated
in vacuo to give the crude product, which was purified by flash chro-
matography (1:1 ethyl acetate:hexanes) to afford the product
(40 mg, 24%) as a colourless oil.
O
(iii)
BocHN
9
Scheme 2. Reagents and conditions: (i) (a) ClCO2t-Bu, NMM, DME, ꢀ10 °C, 10 min;
(b) NaBH4, H2O, 0 °C, 1 min (ii) allyl ethyl carbonate, Pd(Ph3P)4, THF, 40 °C, 1 h (iii).
LiOH (aq.), THF/MeOH, rt, o/n.
½
a 2D0
ꢁ
¼ ꢀ12:0 (c 1.0, CHCl3). IR (CH2Cl2)
m
3436, 2981, 2863,
2253, 2113, 1794, 1710, 1640, 1497, 1366, 1251, 1163 cmꢀ1
.
1H
NMR (300 MHz, CDCl3) d (ppm): 1.46 (s, 9H), 3.55 (dd, J = 9.5,
5.2 Hz, 1H), 3.82 (dd, J = 9.4, 3.6 Hz, 1H), 3.96–4.00 (m, 2H), 4.29
(br s, 1H), 5.19 (dq, J = 10.3, 2.7, 1.2 Hz, 1H), 5.25 (dq, J = 17.2,
3.2, 1.5 Hz, 1H), 5.39 (m, 1H), 5.57 (br s, 1H), 5.85 (ddt, J = 17.1,
10.4, 5.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) d (ppm): 28.6, 54.4,
58.0, 69.9, 72.6, 80.5, 117.8, 134.3, 155.7, 193.2. HRMS (ESI) m/z:
calcd mass for C12H19N3NaO4: 292.1273. Found: 292.1270.
3. Conclusions
In conclusion, we have developed and evaluated two practical
routes to the new b-amino acid, Fmoc-O-allyl-b-serine 1. Although
the second route suffers from losses in the allylation step, it is the
preferred route for scale-up as it avoids the use of hazardous
diazomethane.
4.2. (R)-4-(Allyloxy)-3-(tert-butoxycarbonylamino)butanoic acid 6
4. Experimental
4.1. General
To a solution of diazoketone 5 (105 mg, 0.39 mmol) in THF
(1 mL) and water (1 mL), under an atmosphere of nitrogen and pro-
tected from light, was added a solution of silver trifluoroacetate
(17 mg, 0.078 mmol) in triethylamine (136 lL, 0.795 mmol) at
If dry and air-free conditions were required, reactions were per-
formed in oven-dried glassware (120 °C) under a positive pressure
of nitrogen or argon. NMR spectra were recorded on a Varian 300
or 500 spectrometer or a Bruker AM 300 or Bruker Advance DRX
400 spectrometer. Infrared spectra were recorded on a Perkin
Elmer 1600 Series Fourier Transform spectrometer. High resolution
mass spectra (HRMS) were recorded on a Bruker BioApex 47e
FTMS. Melting points were recorded on an electrothermal melting
point apparatus and are uncorrected.
ꢀ25 °C. The reaction was allowed to warm to room temperature
and stirred overnight. Volatiles were removed in vacuo and satu-
rated aqueous NaHCO3 was added, and the resulting solution was
stirred for 1 h. The aqueous solution was extracted with diethyl
ether, acidified to pH 2 with the addition of 1 M aqueous HCl and ex-
tracted twice with ethyl acetate. The combined organics were
washed with brine, dried over MgSO4 and concentrated in vacuo
to afford the product (81 mg, 80%) as a pale yellow oil, which was
utilised in the next step without further purification.
Silica gel used for flash chromatography was 40–63 lm (230–
½
a 2D0
ꢁ
¼ þ11:0 (c 1.0, CHCl3). IR (neat)
m
3083, 2979, 2932, 1710,
.
400 mesh) silica gel 60 (Merck No. 9385). Dichloromethane
(DCM) was distilled from P2O5. Diethyl ether and tetrahydrofuran
(THF) were distilled from sodium/benzophenone ketyl prior to
use. Dimethylformamide (DMF) was dried over 4 Å molecular
sieves. All other solvents were used as supplied. Commercially
available reagents were used without further purification.
1509, 1394, 1368, 1283, 1242, 1158 cmꢀ1
1H NMR (300 MHz,
CDCl3) d (ppm): 1.44 (s, 9H), 2.67 (m, 2H), 3.49 (dd, J = 9.6,
5.3 Hz, 1H), 3.54 (dd, J = 9.5, 4.2 Hz, 1H), 3.92–4.04 (m, 2H), 4.12
(m, 1H), 5.14 (br s, 1H), 5.18 (dq, J = 10.4, 2.9, 1.3 Hz, 1H), 5.26
(dq, J = 17.3, 3.3, 1.6 Hz, 1H), 5.87 (ddt, 17.2, 10.4, 5.6 Hz, 1H). 13C
NMR (75 MHz, CDCl3) d (ppm): 28.5, 36.3, 47.3, 71.0, 72.3, 79.9,
117.4, 134.5, 155.6, 176.4. HRMS (ESI) m/z: calcd mass for
C12H21NNaO5: 282.1317. Found: 282.1314.
4.1.1. (S)-tert-Butyl 1-(allyloxy)-4-diazo-3-oxobutan-2-ylcarba-
mate 5
Boc-
(2 mL) under an atmosphere of nitrogen and was cooled to ꢀ25 °C.
The N-methylmorpholine (47 L, 0.43 mmol) and ethyl chlorofor-
mate (41 L, 0.43 mmol) were added dropwise, and the resulting
L
-allyl serine 46 (100 mg, 0.41 mmol) was dissolved in THF
4.3. (R)-4-(Allyloxy)-3-aminobutanoic acid, trifluoroacetic acid
salt 10
l
l
To a solution of the above crude 6 (2.70 g, 10.41 mmol) in
CH2Cl2 (145 mL) was added trifluoroacetic acid (73 mL) at 0 °C.
mixture was stirred at this temperature for 1 h. The reaction was
allowed to warm to 0 °C, and diazomethane (generated in situ)

Y. Bergman et al. / Tetrahedron: Asymmetry 19 (2008) 2861–2863
2863
The reaction was stirred for 1 h at room temperature, concentrated
4.6. (R)-Benzyl 4-(allyloxy)-3-(tert-butoxycarbonylamino)-
butanoate 8
in vacuo and freeze dried overnight to afford the trifluoroacetic
acid salt (2.59 g, 91%) as a pale orange oil. ½a D20
¼ þ3:0 (c 1.0,
ꢁ
CHCl3). IR (neat)
m
2924, 1674, 1505, 1479, 1426, 1267, 1202,
Alcohol7(5.00 g, 16.16 mmol)wasdissolvedindegassed(argon),
dry THF (100 mL) under an atmosphere of argon. Allyl ethyl carbon-
ate (2.94 mL, 22.63 mmol) and Pd(Ph3P)4 (375 mg, 0.32 mmol) were
added to the stirring solution. The system was degassed (argon) for a
few minutes, heated to 40 °C and stirred at this temperature for 1 h.
The solution was concentrated in vacuo, and the resulting residue
was purified by flash chromatography (1:4 ethyl acetate:hexanes)
to afford desired product 8 as a viscous, pale yellow oil (2.37 g,
42%). Lactone 9 (1.46 g, 45%) was also obtained as an off-white crys-
1140 cmꢀ1 1H NMR (300 MHz, MeOD) d (ppm): 2.67–2.83 (m,
.
2H), 3.59 (dd, J = 10.2, 6.1 Hz, 1H), 3.67–3.77 (m, 2H), 4.04–4.14
(m, 2H), 5.24 (dm, J = 10.4 Hz, 1H), 5.34 (dm, J = 17.3 Hz, 1H),
5.96 (m, 1H). 13C NMR (75 MHz, MeOD) d (ppm): 34.7, 49.6, 69.9,
73.5, 118.3, 135.4, 173.4. HRMS (ESI) m/z: calcd mass for
C7H14NO3: 160.0974. Found: 160.0969.
4.4. (R)-3-(((9H-Fluoren-9-yl)methoxy)carbonylamino)-4-(allyl-
oxy)butanoic acid 1
talline solid. ½a D20
ꢁ
¼ þ8:0 (c 1.0, CHCl3). IR (neat)
m 3370, 2978, 1715,
1500, 1456, 1366, 1247 cmꢀ1
.
1H NMR (400 MHz, CDCl3) d (ppm):
1.43 (s, 9H), 2.62–2.70 (m, 2H), 3.46 (dd, J = 9.4, 5.2 Hz, 1H), 3.51
(dd, J = 9.5, 4.1 Hz, 1H), 3.88–3.98 (m, 2H), 4.14 (m, 1H), 5.12 (s,
2H), 5.13 (br s, 1H), 5.15 (dq, J = 10.4, 3.0, 1.3 Hz, 1H), 5.22 (dq,
J = 17.2, 3.3, 1.8 Hz, 1H), 5.84 (ddt, 17.2, 10.4, 5.6 Hz, 1H), 7.29–
7.37 (m, 5H). 13C NMR (100 MHz, CDCl3) d (ppm): 28.3, 36.4, 47.5,
66.4, 71.0, 72.1, 79.4, 117.0, 128.2, 128.4, 128.6, 134.5, 136.0,
155.2, 171.3. HRMS (ESI) m/z: calcd mass for C19H27NNaO5:
372.1787. Found: 372.1780.
To the amine salt 10 (2.50 g, 9.15 mmol), a 10% aqueous solution
of Na2CO3 was added until the pH of the resulting solution was 10. It
was cooled to 0 °C, and Fmoc–OSu (3.70 g, 10.98 mmol) in acetone
(115 mL) was added. The reaction was stirred at room temperature
overnight. Volatiles were removed in vacuo, and the resulting aque-
ous solution was diluted with water and ethyl acetate. The layers
were separated, and the aqueous layer was acidified to pH 2 with
the addition of 2 M aqueous HCl and extracted twice with ethyl ace-
tate. The combined organics were washed with brine, dried over
Na2SO4 and concentrated in vacuo to afford a pale yellow oil. The
oil was lyophilised from acetonitrile/water (50:50) to afford 1
4.7. (R)-tert-Butyl 5-oxotetrahydrofuran-3-ylcarbamate 9
Mp 113–115 °C. ½a D20
ꢁ
¼ þ56:0 (c 1.0, CHCl3). IR (neat)
m
3357,
1H
(3.35 g, 96%) as an off-white solid. Mp 69–71 °C. ½a D20
¼ þ11:0 (c
ꢁ
2981, 2931, 1781, 1700, 1507, 1457, 1369, 1253, 1169 cmꢀ1
.
1.0, CHCl3). IR (neat)
m .
3322, 3018, 1710, 1517, 1450, 1219 cmꢀ1
NMR (300 MHz, CDCl3) d (ppm): 1.44 (s, 9H), 2.44 (dd, J = 18.0,
4.2 Hz, 1H), 2.82 (dd, J = 17.9, 7.7 Hz, 1H), 4.20 (dd, J = 9.1, 2.8 Hz,
1H), 4.45 (m, 1H), 4.49 (dd, J = 10.9, 5.9 Hz, 1H), 4.95 (br s, 1H).
13C NMR (75 MHz, CDCl3) d (ppm): 28.4, 35.2, 47.9, 73.8, 80.8,
155.2, 175.1. HRMS (ESI) m/z: calcd mass for C9H15NNaO4:
224.0899. Found: 224.0894.
1H NMR (300 MHz, CDCl3) d (ppm): 2.69 (m, 2H), 3.55 (m, 2H),
3.98 (m, 2H), 4.22 (m, 2H), 4.40 (m, 2H), 5.19 (dd, J = 10.4, 1.0 Hz,
1H), 5.25 (d, J = 17.3 Hz, 1H), 5.41 (bd, J = 6.8 Hz, 1H), 5.87 (m, 1H),
7.31 (dt, J = 7.4, 1.2 Hz, 2H), 7.39 (t, J = 7.3 Hz, 2H), 7.58 (d,
J = 7.3 Hz, 2H), 7.75 (d, J = 7.4 Hz, 2H). 13C NMR (75 MHz, CDCl3) d
(ppm): 36.1, 47.4, 47.9, 67.1, 70.8, 72.3, 117.5, 120.1, 125.2, 127.2,
127.8, 134.3, 141.5, 144.0, 156.1, 176.4. HRMS (ESI) m/z: calcd mass
for C22H23NNaO5: 404.1474. Found: 404.1472.
4.8. (R)-4-(Allyloxy)-3-(tert-butoxycarbonylamino)butanoic
acid 6
Benzyl ester 8 (3.60 g, 10.30 mmol) was dissolved in THF (90 mL)
and methanol (9 mL) under an atmosphere of nitrogen and was
cooled to 0 °C. An aqueous solution of LiOH (69 mL, 1.5 M,
103.0 mmol)was added slowly, and the reactionmixture was stirred
at room temperature overnight. Volatiles were removed in vacuo,
and water and ethyl acetate were added. The layers were separated,
and the aqueous layer was acidified to pH 2 with the addition of 2 M
aqueous HCl and extracted twice with ethyl acetate. The combined
organics were washed with brine, dried over Na2SO4 and concen-
trated in vacuo to afford the product (2.54 g, 98%) as a pale yellow oil.
4.5. (R)-Benzyl 3-(tert-butoxycarbonylamino)-4-hydroxy-
butanoate 7
To a stirred solution of Boc-D-aspartic acid 4-benzyl ester 3
(5.00 g, 15.47 mmol) in DME (15 ml) were added N-methylmorpho-
line (1.70 mL, 15.47 mmol) and isobutyl chloroformate (2.02 mL,
15.47 mmol) at ꢀ10 °C. Upon stirring at this temperature for
10 min, the precipitated N-methyl morpholine hydrochloride salt
was removed by filtration and the solid was washed with DME.
The combined filtrate was placed in a large conical flask and was
cooled to 0 °C, and a solution of NaBH4 (0.88 g, 23.26 mmol) in water
(8 mL) was added in one portion resulting in evolution of gas. Addi-
tional water (400 mL) was added immediately afterwards and the
product precipitated out of solution. Ethyl acetate was added, the
layers were separated, and the organic layer was washed with brine,
dried over Na2SO4, filtered and concentrated in vacuo. The resulting
oily residue was freeze dried overnight to afford the product (4.54 g,
95%) as a whitesolid, which was utilised in the next step withoutfur-
References
1. Seebach, D.; Lelais, G.; Micuch, P.; Josien-Lefebvre, D.; Rossi, F. Helv. Chim. Acta
2004, 87, 3131.
2. Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. J. Am. Chem.
Soc. 1980, 102, 6163.
3. Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J. Tetrahedron Lett.
1991, 32, 923.
4. Haight, A. R.; Stoner, E. J.; Peterson, M. J.; Grover, V. K. J. Org. Chem. 2003, 68,
ther purification. Mp 62–64 °C. ½a D20
ꢁ
¼ ꢀ14:0 (c 1.0, CHCl3). IR (neat)
8092.
m
3400, 2978, 1693, 1512, 1456, 1392, 1367, 1250, 1168 cmꢀ1 1H
.
5. For leading references on stapled
a-peptides see: Boal, A. K.; Guryanov, I.;
Moretto, A.; Crisma, M.; Lanni, E. L.; Toniolo, C.; Grubbs, R. H.; O’Leary, D. J. J. Am.
Chem. Soc. 2007, 129, 6986.
6. Miyoshi, M.; Sugano, H. J. Org. Chem. 1976, 41, 2352; Blackwell, H. E.; Sadowsky,
J. D.; Howard, R. J.; Sampson, J. N.; Chao, J. A.; Steinmetz, W. E.; O’Leary, D. J.;
Grubbs, R. H. J. Org. Chem. 2001, 66, 5291.
7. Cesar, J.; Sollner-Dolenc, M. Tetrahedron Lett. 2001, 42, 7099.
8. Ueno, M.; Kitagawa, H.; Ishitani, H.; Yasuda, S.; Hanada, K.; Kobayashi, S.
Tetrahedron Lett. 2001, 42, 7863.
NMR (400 MHz, CDCl3) d (ppm): 1.43 (s, 9H), 2.61 (br s, 1H), 2.63–
2.70 (m, 2H), 3.68 (s, 1H), 3.69 (s, 1H), 4.00 (m, 1H), 5.13 (s, 2H),
5.20 (br s, 1H), 7.30–7.38 (m, 5H). 13C NMR (100 MHz, CDCl3) d
(ppm): 28.4, 36.1, 49.5, 64.6, 66.7, 79.9, 128.3, 128.4, 128.6, 135.6,
155.8, 171.6. HRMS (ESI) m/z: calcd mass for C16H23NNaO5:
332.1474. Found: 332.1474.