Synthesis of Fmoc-β-homoamino acids by ultrasound-promoted wolff rearrangement

Article abstract of DOI:10.1055/s-1998-2075

A highly efficient protocol for Amdt-Eistert chain elongation of the base-labile fluorenylmethoxycarbonyl (Fmoc) protected α-amino acids by Ag⁺- catalyzed, ultrasound-promoted Wolff rearrangement of the corresponding α- diazo ketones at room temperature is described. The enantiomeric purity of the products was examined by capillary zone electrophoresis with chiral buffer systems.

Full text of DOI:10.1055/s-1998-2075

PAPERS
837
b
Synthesis of Fmoc- -Homoamino Acids by Ultrasound-Promoted Wolff
Rearrangement1
Annett Müller,a Carla Vogt,b Norbert Sewald*a
a Institut für Organische Chemie der Universität Leipzig, Talstraße 35, D-04103 Leipzig, Germany
E-mail: sewald@organik.orgchem.uni-leipzig.de
b Institut für Analytische Chemie der Universität Leipzig, Linnéstr. 3, D-04103 Leipzig, Germany
Received 11 August 1997; revised 18 November 1997
Dedicated to Prof. Dr. Klaus Burger on the occasion of his 60th birthday
Abstract: A highly efficient protocol for Arndt–Eistert chain a-amino acids according to the Arndt–Eistert procedure
elongation of the base-labile fluorenylmethoxycarbonyl (Fmoc)
giving standard b-homoamino acids in only two steps
protected a-amino acids by Ag+-catalyzed, ultrasound-promoted
nicely complements the synthetic repertoire.
Wolff rearrangement of the corresponding a-diazo ketones at
room temperature is described. The enantiomeric purity of the
products was examined by capillary zone electrophoresis with
chiral buffer systems.
Silver oxide catalysis usually involves a heterogeneous
reaction at higher temperatures. This procedure has often
been replaced by the Newman–Beal protocol6 consisting
of a homogeneous, Ag+-catalyzed decomposition, in the
Key words: Fmoc-b-homoamino acids, Wolff rearrangement,
sonochemistry, capillary zone electrophoresis
presence of several equivalents of a tertiary base, proceed-
ing at considerably lower temperature.9 A SET-initiated
radical chain mechanism has been postulated.19 Alterna-
tively, a diazo ketone–Ag(NEt3)n complex may be in-
volved, which is formed upon deprotonation of the diazo
ketone. The presence of a base has, therefore, often been
assumed to be inevitable for the reaction progress.19 How-
ever, the reaction results in low yield in the case of Fmoc-
protected amino acids because of the eminent sensitivity
of the Fmoc group towards basic conditions.
The homologation of a-amino acids is an important strat-
egy for the asymmetric synthesis of b-homoamino acids,2
as well as addition of nitrogen nucleophiles to a,b-unsat-
urated esters,3 enolate additions to imines, and hydrogena-
tion reactions of b-enamino esters.
The Arndt–Eistert approach towards b-homoamino acids
via Wolff rearrangement of diazo ketones derived from N-
phthaloyl-,4 N-tosyl-,5 or N-Cbo/Boc-protected6 a-amino
acids has been utilized since the early 1950s.7, 8 Recently,
this protocol was reinvestigated thoroughly with respect
to possible epimerization of the chiral center9 and to the
potential synthetic utility of the ketene intermediate.10
The Wolff rearrangement of a-diazo ketones can be ac-
complished thermally, photochemically, or by metal ion
(Ag+) catalysis and has been shown to proceed with com-
plete retention of the configuration.9, 11 Epimerization (ap-
proximately 10%) occurs only in the case of carbamate-
protected phenylglycine, presumably during carboxylic
group activation.9, 12
While this manuscript was in preparation, a publication
described a base-free, silver ion catalyzed Wolff rear-
rangement of Fmoc-protected b-amino acids.20 This reac-
tion proceeds at elevated temperatures and the possible
epimerization has been examined only in the case of
(2S,3S)-isoleucine using 13C NMR spectroscopy, which is
intrinsically too insensitive for this purpose.20
The Ag+/base-catalyzed reaction of simple diazo ketones
(e.g. diazoacetophenone) is reported to be promoted sub-
stantially by sonication.21 We found that a base-free, Ag+-
catalyzed Wolff rearrangement of 2 proceeds smoothly
within minutes at room temperature on sonication using
an ultrasound cleaning bath.
There has been a growing interest in the structural features
of peptides containing b-homoamino acids. However,
only peptides containing b-alanine together with a-amino
acids,13 a few peptides containing exclusively or mainly
b-homoamino acids14 or poly[(a-alkyl)-b-L-aspartate]s15
have been examined until now. Peptides containing b-ho-
moamino acids are often characterized by lower rates of
metabolic degradation.8
The Fmoc-protected a-amino acids are activated as mixed
anhydrides using ethyl chloroformate. Reaction with a
sufficiently high excess of diazomethane (approx. 3
We have developed routes for the asymmetric synthesis of
b-homoamino acids by Michael addition of homochiral
amidocuprates to a,b-unsaturated esters and of a-deuterio
b-homoamino acids or a-alkyl b-homoamino acids by
tandem Michael addition/ester enolate trapping.16 In the
course of our investigation into secondary structure ele-
ments caused by the replacement of single a-amino acids
by enantiomerically pure b-homoamino acids in physio-
logically active peptides, we required Fmoc-protected b-
homoamino acids17 for solid phase peptide synthesis
(SPPS).18 For simple derivatives, the chain elongation of
Scheme

838
Feature Article
SYNTHESIS
Table 1. Physical Data of Fmoc-Protected b-Amino Acids 3
Compound22
CIP23
ee
(%)
Yielda
(%)
mp
(°C)
[a]D
(°C, c, Solvent)
Molecular
Formulac
Fmoc-D-b-HPhg-OH (3a)
[Fmoc-D-b-Phe-OH]
S
80.5
CZE
70
184
–22.2 (24, 1.0,
DMF)
C24H21NO4
(387.44) · 0.5 H2O
Fmoc-D-b-HPhe-OH (3b)
R
S
82 (Lit. 4620) 127 (Lit. oil20)
+26.9 (28, 0.6,
MeOH)
C25H23NO4
(401.46)
Fmoc-L-b-HPhe-OH (3b)
>99
CZE
76
125
–25.0 (28, 0.6,
MeOH)
Fmoc-L-b-HVal-OH (3c)
[Fmoc-L-b-Leu-OH]
R
S
70 (Lit. 77,20
6124)
157 (Lit. 153–154,20 +8.0 (27, 0.5,
C21H23NO4
(353.42) · 0.5 H2O
154–15524)
MeOH)h
Fmoc-L-b-HLeu-OH (3d)
77 (Lit. 7920) 99 (Lit. 108–11020)
–12.0 (26, 1.0,
MeOH)
C22H25NO4
(367.44)
Fmoc-L-b-HIle-OH (3e)
R
R
65 (Lit. 6420) 138 (Lit. 99–l0020)
+3.7 (28, 4.0,
MeOH)
C22H25NO4
(367.44) · 0.5 H2O
Fmoc-L-b-HAsp(O-tBu)-OH (3f)
[Fmoc-L-b-Glu(O-tBu)-OH]
80
88
+0.3 (28, 1.9,
MeOH)
C24H27NO6
(425.48)
a Overall yield starting from Fmoc-a-amino acids.
b [a]D27 –17.9 (0.6, CHCl3); Lit.24 [a]D27 –21.5 (0.46, CHCl3).
c Elemental analysis C ± 0.49, H ± 0.47, N ± 0.40.
equiv) secures complete conversion into the diazo ketone,
although it has been reported that the application of this
protocol to Fmoc-protected substrates does not give satis-
factory results.20 The diazo ketones do not require further
purification. Methyl esters of the starting material or other
byproducts have not been observed by 1H NMR spectro-
scopy. Sonication of the diazo ketone in 1,4-dioxane in
the presence of silver benzoate and a suitable hetero nu-
cleophile (water, alcohols, etc.) results in a clean forma-
tion of the b-amino acid derivative. The 1H NMR spectra
and HPLC profiles of the crude reaction mixtures reveal
that no significant byproducts are formed. b-Amino acids
the mild, base-free reaction conditions of our sonochemi-
cal procedure let us conclude that no substantial epimer-
ization should occur (except for phenylglycine).
Nevertheless, we examined the degree of racemization us-
ing capillary zone electrophoresis (CZE) with chiral buff-
er systems. As expected according to previous findings,9
considerable racemization (9–10%) is observed in the
case of 3a (Figure 2), because phenylglycine is prone to
epimerization when the carboxy group is being activated
as mixed anhydride. Figure 1 displays the separation of ra-
cemic 3a.
obtained via this route can be used for peptide synthesis Both enantiomers of b-homophenylalanine have been ex-
without further purification. Literature precedence9 and amined as representatives for the other Fmoc-protected b-
Figure 1. CZE analysis of racemic 3a.
Figure 2. CZE analysis of of D-3a.

June 1998
SYNTHESIS
839
amino acid derivatives synthesized; they are obtained
enantiomerically pure as shown in Figure 4 (L-3b). The
trace given in Figure 3 arises from a sample obtained by
arbitrarily mixing both enantiomers of 3b. Further addi-
tion of D-3b to the mixture causes an increase in intensity
of the first peak. Hence, D-b-homophenylalanine migrates
faster than L-b-homophenylalanine. Therefore, even
small quantities of the D enantiomer would inevitably
have been detected on CZE of L-3b.
Figure 4. CZE analysis of L-3b.
297 K and were calibrated against internal standards (TMS and/or
solvent). Optical rotation indices were obtained with a Polartronic-D
polarimeter (Schmidt & Haensch); FT-IR spectra were recorded on an
ATI Genesis spectrometer using KBr pellets, the data are given in
wavenumbers (cm–1). FAB mass spectra were recorded on a VG
ZAB-HSQ and EI MS was done on a VG 12-250 instrument (70eV).
Microanalyses were performed by the faculty’s microanalytical labo-
ratory on a Heraeus CHN-O-RAPID elemental analyzer. A Beckman
P/ACE 2100 instrument with a fixed wavelength detector (214 nm,
5 Hz) was used for capillary zone electrophoresis. Racemic b-phenyl-
alanine was commercially available (Aldrich).
Figure 3. CZE analysis of scalemic 3b (arbitrary DL mixture). The D
enantiomer migrates faster than the L enantiomer.
Synthesis of Fmoc-Protected b-Homoamino Acids; General Pro-
cedure:
An ultrasound cleaning bath Bandelin Sonorex RK 510 H was used
for the sonochemically promoted Wolff rearrangement. Analytical
TLC was performed using silica gel 60 F254 plates on aluminum foil;
silica gel 60 (32–60 mm) was used for flash chromatography. The pu-
rity of the Fmoc-protected b-amino acids was checked by HPLC
(MeCN/water/TFA gradient on RP-l8 column). Mps were deter-
mined with an apparatus according to Tottoli and are uncorrected.
NMR spectra were recorded on Varian Gemini 200 or Gemini 2000
instruments, in acetone-d6 at 200 MHz (1H) and 50 MHz (13C), at
The Fmoc-protected a-amino acid derivative (5–l5 mmol) was dis-
solved in anhyd THF (5 mL/mmol). NEt3 (1 equiv) and ethyl chloro-
formate (1 equiv) were added sequentially at –15°C. Stirring was
continued for 15 min at the same temperature, then the solution was
warmed up to 0°C. A solution of diazomethane (3 equiv, CAUTION)
in Et2O was added slowly at 0°C. The slightly yellow solution was al-
lowed to reach r.t. and was stirred for a further 3 h. Excess diazo-
methane was decomposed by dropwise addition of HOAc. The
Table 2. 1H NMR Data for Fmoc-Protected b-Amino Acids 3
Product
1H NMR d, J (Hz)
3a
2.80 (dd, J = 6.6, 15.5, 1H, Ha), 2.91 (dd, J = 7.8, 15.5, 1H, Ha), 4.13–4.31 (m, 3H, Fmoc CH2, CH), 5.17 (dd, J = 6.6, 7.8,
1H, Hb), 7.20–7.42 (m, 9H, Har), 7.62 (m, 2H, Ha), 7.78 (m, 2H, Har)
3b
3c
3d
2.55 (m, 2H, Ha), 2.91 (m, 2H, Hg), 4.1 4–4.31 (m, 4H, Hb, Fmoc CH2, CH), 6.52 (br, 1H, NH), 7.16–7.45 (m, 9H, Har), 7.65
(m, 2H, Har), 7.86 (m, 2H, Har)
0.94 (d, J= 6.7, 6H, Hd), 1.88 (m, 1H, Hg), 2.47 (dd, J= 8.0, 15.4, 1H, Ha), 2.58 (dd, J = 5.5, 15.4, 1H, Ha), 3.90 (m, 1H, Hb),
4.17–4.33 (m, 3H, Fmoc CH2, CH), 6.43 (br d, J = 10.0, 1H, NH), 7.27–7.46 (m, 4H, Har), 7.68 (m, 2H, Har), 7.85 (m, 2H, Har)
0.95 (d, J= 6.7, 3H, He), 0.97 (d, J = 6.7, 3H, He), 1.38 (ddd, J = 4.5, 9.2, 13.7, 1H, Hg), 1.60 (ddd, J = 4.4, 9.3, 13.7, 1H, Hg),
1.75 (m, 1H, Hd), 2.50 (dd, J = 6.9, 15.4, 1H, Ha), 2.56 (dd, J = 6.6, 15.4, 1H, Ha), 4.13 (m, 1H, Hb), 4.26–4.37 (m, 3H, Fmoc
CH2, CH), 6.40 (d, J = 8.8, 1H, NH), 7.33–7.47 (m, 4H, Har), 7.72 (m, 2H, Har), 7.89 (m, 2H, Har)
3e
3f
0.92 (t, J = 6.8, 3H, He), 0.93 (d, J = 6.4, 3H, CH3), 1.22 (m, 1H, Hd), 1.57 (m, 1H, Hd), 1.66 (m, 1H, Hg), 2.46 (dd, J = 8.0,
15.3, 1H, Ha), 2.56 (dd, J = 5.0, 15.3, 1H, Ha), 4.00 (m, 1H, Hb), 4.13–4.34 (m, 3H, Fmoc CH2, CH), 6.46 (d, J = 8.8, 1H,
NH), 7.25–7.44 (m, 4H, Har), 7.69 (m, 2H, Har), 7.85 (m, 2H, Har)
1.43 (s, 9H, OtBu), 2.57–2.67 (m, 4H, Ha, Hg), 4.22–4.41 (m, 4H, Hb, Fmoc CH2, CH), 6.55 (br, 1H, NH), 7.27–7.45 (m, 4H,
Har), 7.68 (m, 2H), 7.85 (m, 2H, Har)

840
Feature Article
SYNTHESIS
Table 3.13C NMR, IR, and MS Data for Fmoc-Protected b-Amino Acids 3
Product
13C NMR d
IR n (cm–1)
MS m/z
3a
3420 (br), 1705
FAB: 410 (M+Na)+, 388 (M+H)+, 329,
307, 289, 178, 165, 154, 136
41.31, 48.00, 52.86, 66.89, 120.72, 126.03, 127.32,
127.87, 128.00, 128.42, 129.23, 142.03, 143.47, 144.98,
156.31, 172.00
3b
3403 (br), 3341, 1703
FAB: 424 (M+Na)+, 402 (M+H)+, 307,
289, 191, 180, 179, 178, 165, 154, 136
38.62, 40.63, 47.75, 50.52, 66.43, 120.54, 125.88,
126.92, 127.67, 128.24, 128.92, 131.03, 139.31, 141.88,
144.91, 156.20, 172.55
3c
3404, 1700
EI: 353 (M)+, 311, 267, 196, 179, 178,
165, 152, 139, 69, 42
18.42, 19.44, 32.80, 37.30, 48.11, 54.41, 66.75, 120.82,
126.18, 127.97, 128.53, 142.17, 145.33, 156.90, 173.19
3d
3433 (br), 1704
FAB: 390 (M+Na)+, 368 (M)+, 191,
180, 179, 178, 165, 154, 136
21.62, 23.14, 25.03, 40.24, 44.10, 46.88, 47.70, 66.18,
120.40, 125.75, 127.53, 128.10, 141.76, 144.88, 156.27,
172.43
3e
3f
3323, 1697, 1542
3404, 1700
FAB: 390 (M+Na)+, 368 (M+H)+, 191,
180, 179, 178, 165, 146, 130
11.41, 14.94, 25.63, 36.08, 39.02, 47.67, 52.84, 66.31,
120.34, 125.77, 127.53, 128.10, 141.74, 144.90, 156.32,
172.90
FAB: 448 (M+Na)+, 426 (M+H)+, 392,
370, 179, 178, 165, 148
28.59, 39.27, 41.01, 46.85, 48.43, 67.29, 81.29, 121.15,
126.48, 128.28, 128.85, 142.46, 145.48, 156.66, 171.15,
172.78
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