Synthesis of N-urethane protected β-amino alcohols employing N-(protected-α-aminoacyl)benzotriazoles

Article abstract of DOI:10.3184/030823407X272985

A simple and racemisation-free synthesis of N-urethane protected α-amino/peptidyl alcohols by the reduction of the corresponding easily accessible N-acylbenzotriazoles is described. The method is practical, straightforward, fast and efficient for the synt

Full text of DOI:10.3184/030823407X272985

JOURNAL OF CHEMICAL RESEARCH 2007
DECEMBER, 683–685
RESEARCH PAPER 683
Synthesis of N-urethane protected β-amino alcohols employing
N-(protected-α-aminoacyl)benzotriazoles
Vommina V. Sureshbabu*, N.S. Sudarshan, L. Muralidhar and N. Narendra
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University,
Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India
A simple and racemisation-free synthesis of N-urethane protected a-amino/peptidyl alcohols by the reduction of the
corresponding easily accessible N-acylbenzotriazoles is described. The method is practical, straightforward, fast and
efficient for the synthesis of amino/peptidyl alcohols. All the alcohols made were isolated in high yields and purity.
Keywords: β-aminoalcohols, N-protecting groups, amino acids, benzotriazoles, sodium borohydride, reduction
N-Protected amino alcohols and peptidyl alcohols are
important synthetic intermediates,1 especially useful in the
synthesis of amino/peptidyl aldehydes which have diverse
synthetic as well as biological applications.2,3 Several peptides
including enkephalins have been shown to exhibit better
biological activity upon reduction of the terminal carboxylic
group into the corresponding alcohol.4 The N-protected
amino alcohols are also used in the synthesis of peptides
possessing reduced peptide bonds5 and in the preparation of
stereochemically defined methylene-oxydipeptides.6 They are
also key intermediates in the synthesis of vicinal diamines,
ureidopeptides,7 oxazolidinones, peptidosulfinamides, and
peptidosulfonamides.8 Moreover, oligopeptidyl carbamates9
as well as peptidyl carbonates are assembled starting from
β-aminoalcohol building blocks.
The aminoalcohols are widely prepared by borane-
mediated reduction of N-protected amino acids.3 They are also
synthesised by the reduction of the corresponding alkyl esters
or active esters10 with NaBH4. Kokotos11a and Rodriguez
et al.11b have reported the chemoselective reduction of
mixed carboxylic anhydrides generated by the reaction of
N-protected amino acid with ethyl chloroformate or isobutyl
chloroformate in presence of a base. Similarly, urethane-
protected N-carboxyanhydrides (UNCAs)12 and various acid
fluorides13 are also reduced into alcohols using NaBH4. On
the other hand, there are several reports describing the use
of reducing agents such as LiAlH4,14 DIBAL,15 etc., for such
reductions.
acylbenzotriazoles using NaBH4 to form the corresponding
alcohols. During peptide synthesis, the amino group is usually
protected with any one of the urethane type groups, Boc,
Z, Fmoc and Bsmoc which differ from one another in their
deprotection conditions. Boc and Z groups are deprotected
using acidolysis whereas Fmoc and Bsmoc groups are
deprotected using an organic base. We herein describe a
general route for the reduction of α-amino acids carrying with
all four commonly employed amine protecting groups.
Results and discussion
N-Protected amino acylbenzotriazoles are accessible in
excellent yields by reacting the corresponding amino acid or
peptide acid with a solution of benzotriazole pretreated with
SOCl2.17 In a typical procedure, the N-acylbenzotriazoles
were treated with NaBH4 in MeOH at room temperature to
accomplish their conversion to the corresponding alcohol.
The reduction was found to be very fast, being complete
within 2 min. In many cases, the product separated out as a
solid after the reaction. Consequently, the reaction mixture
was diluted with water and the products were filtered and
isolated. A regular aqueous workup method was also followed
to isolate the products which could not be precipitated out
from the reaction mixture (Scheme 1).
All the protected amino alcohols were obtained in excellent
yield (95–99%). In the case of bifunctional amino acids the
side chain protecting group such as tertiary butyl ester of Asp/
Glu, a benzyl ether linkage on Ser/Thr remained unaffected
during reduction. In order to demonstrate the versatility of
this protocol, a series of Fmoc, Boc, Z and Bsmoc protected
amino acids were converted into the corresponding alcohols
(Table 1).
The protocol was then extended to the synthesis of
N-protected peptide alcohols. The peptide acids were
synthesised by coupling with O,N-bis-trimethylsilyl amino
acid with mixed anhydride of N-protected amino acid.20 They
were then converted into the corresponding acylbenzotriazole
derivatives and further reduced to the corresponding alcohols
using NaBH4 following the same procedure (Scheme 2).
The reaction was also tested for racemisation by recording
the 1H NMR spectra of compounds 4 and 5 (Table 1)
synthesised via the present protocol. Compound 4 contained
a doublet at δ 1.163, 1.180 while its epimer 5 showed the
Katritzky et al. have accomplished pioneering work on the
synthesis of stable N-acylbenzotriazoles and they demonstrated
their wide range of applications in organic synthesis.16 In
peptide chemistry, N-acylbenzotriazole derivatives of amino
acids have been used to acylate unprotected amino acids
under aqueous reaction conditions to obtain peptide acids,17
prepare N-protected α-amino acid azides,18 hydroxamic acids
and peptide heterocycles such as oxadiazoles.19 The utility of
N-acylbenzotriazoles as activated precursors for the synthesis
of aminoalcohols is to the best of our knowledge yet to be
demonstrated.
The present work describes the simple and selective
reduction of N-t-butoxycarbonyl (Boc)/benzyloxycarbonyl
(Z)/9-fluorenylmethoxycarbonyl
(Fmoc)/1,1-dioxobenzo-
thiophen-2-ylmethyloxycarbonyl (Bsmoc) amino acid-derived
R1
R1
R1
NaBH4 / MeOH
1. Benzotriazole
PgHN
Pg= Fmoc/ Boc/ Z/ Bsmoc
Scheme 1 Synthesis of N-protected b-aminoalcohols from N-(Pg-a-aminoacyl)benzotriazoles.
* Correspondent. Email: hariccb@rediffmail.com
COOH
PgHN
COBt
PgHN
CH2OH
2. SOCl2
PAPER: 07/4808

684 JOURNAL OF CHEMICAL RESEARCH 2007
Table 1 Preparation of N-protected amino and peptide alcohols
Compd
Protected amino or
peptide alcohol
Yield/%
M.p./°C
[a]24
ES-MS
D
(c = 1, CHCl3)
(M + 1)+
1
2
Fmoc-Leu-ol
94
90
91
89
91
89
90
86
81
94
82
91
86
70
72
131
97
–20.8
–6.5
340
398
507
431
431
252
308
296
381
286
344
282
281
298
374
Fmoc-Asp(OtBu)-ol
Fmoc-Phg-Phe-ol
Fmoc-L-Phg-Ala-ol
Fmoc-D-Phg-Ala-ol
Boc-Phe-ol
3
137
126
128
94
–24.6
–20.6
+21.1
–21.6
+12.0
+12.1
–11.6
–12.1
–29.1
–18.2
–29.4
–5.45
–30.1
4
5
6
7
Boc-Thr(Bzl)-ol
Boc-Ser(Bzl)-ol
Boc-Asp(OBzl)-Ala-ol
Z-Phe-ol
Z-Asp(ol)OBzl
Z-Glu(OMe)-ol
Z-Ala-Ala-ol
oil
8
58
9
80
10
11
12
13
14
15
88
gum
69
144
gum
gum
Bsmoc-Ala-ol
Bsmoc-Phe-ol
Fmoc-Leu-ol (1): NMR (CDCl3): δH 0.93 (d, 6H, J = 5.4 Hz), 1.33
(m, 2H), 1.63 (m, 1H), 2.34 (br s, 1H), 3.55 (br m, 2H), 3.77 (m,
1H), 4.19 (t, 1H, J = 6.6 Hz), 4.41 (m, 2H), 5.08 (d, 1H, J = 8.8 Hz),
7.27–7.40 (m, 4H), 7.56 (d, 2H), 7.77 (d, 2H); δC 22.0, 23.0, 24.6,
40.3, 47.2, 51.2, 65.5, 66.4, 119.8, 124.9, 126.9, 127.6, 141.2, 143.8,
156.7. Anal. Calcd for C21H25NO3: C, 74.31, H, 7.42, N, 4.13, Found,
C, 74.30, H, 7.38, N, 4.09%.
R1
R1
1. Benzotriazole
2. SOCl2
H
N
H
N
COOH
PgHN
PgHN
OH
R2
3. NaBH4 / MeOH
O
R2
O
Pg= Fmoc / Boc / Z / Bsmoc
Scheme 2 Synthesis of alcohols from
N-(Pg-a-aminopeptidyl)benzotriazoles.
Fmoc-Phg-Phe-ol (3): 1H NMR (δ, CDCl3): 2.07 (s, 1H), 2.87 (d,
2H, J = 6.4 Hz), 3.60 (m, 2H), 3.96 (m, 1H), 4.16 (t, 1H, J = 6.80
Hz), 4.4 (m, 3H), 5.91 (s, 1H), 7.10–7.40 (m, 14H), 7.56 (m, 2H),
7.77 (d, 2H, J = 7.6 Hz): δC 37.3, 47.2, 54.1, 64.0, 66.7, 68.5, 120.0,
124.7, 125.0, 126.2, 126.5, 126.9, 127.0, 127.2, 128.2, 130.8, 132.7,
139.1, 141.5, 143.9, 156.4, 166.7. Anal. Calcd for C32H30N2O4: C,
75.87, H, 5.97, N, 5.53, Found, C, 75.81, H, 5.98, N, 5.50%.
Boc-Ser(Bzl)-ol (8): NMR (CDCl3): δH 1.40 (s, 9H), 3.50–3.95 (m,
5H), 4.48 (s, 2H), 7.35 (s, 5H); δC 28.2, 59.4, 65.4, 67.1, 73.7, 81.1,
128.1, 128.0, 128.1, 128.3, 138.1, 156.1. Anal. Calcd for C15H23NO4:
C, 64.03, H, 8.24, N, 4.98, Found, C, 64.00, H, 8.30, N, 4.94%.
Z-Phe-ol (10): NMR (CDCl3): δH 2.91 (d, 2H), 2.80 (br, H), 3.55
(m, 2H), 3.71 (br, 1H), 5.05 (s, 2H), 5.61 (s, 1H), 7.30 (s, 5H), 7.35
(s, 5H); δC 37.2, 54.1, 62.6, 64.0, 127.2, 127.57, 127.75, 128.10,
128.5, 136.5, 136.9, 156.6. Anal. Calcd for C17H19NO3: C, 71.56, H,
6.71, N, 4.91, Found, C, 71.50, H, 6.77, N, 4.99%.
Bsmoc-Ala-ol (14): NMR (CDCl3): δH 1.25 (3H, d, J = 7.2 Hz),
3.32 (1H, m), 3.71 (2H, d, J = 6.9 Hz), 5.10 (2H, s), 5.54 (1H, s),
7.15 (1H, s), 7.34 (1H, d, J = 7.0 Hz), 7.49 (2H, m), 7.71 (1H, d,
J = 7.2 Hz); δC 17.4, 47.1, 66.3, 67.2, 121.3, 125.8, 126.3, 127.8,
130.6, 134.1, 137.0, 156.9. Anal. Calcd for C13H15NO5S: C, 52.51, H,
5.09, N, 4.71, Found, C, 52.79, H, 5.10, N, 4.80%.
Bsmoc-Phe-ol (15): NMR (CDCl3): δH 2.93 (2H, d, J = 4.9 Hz),
3.48 (2H, d(d)), 3.87 (1H, m), 5.1 (2H, s), 7.15 (1H, s), 7.33 (1H, d,
J = 6.9 Hz), 7.49 (2H, m), 7.71 (1H, d, J = 7.1 Hz); δC 37.9, 47.3,
52.7, 66.9, 121.3, 125.8, 126.3, 127.8, 128.5, 128.6, 129.8, 130.6,
134.1, 137.0, 139.6, 140.6, 156.9. Anal. Calcd for C19H19NO5S:
C, 61.11, H, 5.13, N, 3.75, Found, C, 61.19, H, 5.18, N, 3.81%.
peaks at δ 1.179, 1.196. The equimolar mixture of 4 and 5,
intentionally mixed, had two doublets at the different values
δ 1.161, 1.174, 1.181, 1.194. This clearly demonstrated that
the method described to make β-amino alcohols is
racemisation-free.
In conclusion, we have developed an efficient method for
the conversion of N-urethane protected amino acids/peptide
acids into the corresponding β-amino alcohols using N-
acylbenzotriazoles. The reduction is rapid, high yielding and
proceeds with no side reactions or racemisation. Common
side chain protecting groups remain unaffected. The present
method is advantageous as it utilises acylbenzotriazoles which
are easy to make and stable to store as C-activated precursors.
Further, since the benzotriazoles of all common N-protecting
groups can be prepared as shelf stable solids in good yield, the
current method becomes a general protocol for reduction of
N-urethane protected amino acids and peptide acids.
Experimental
Melting points were determined by the capillary method. IR spectra
were recorded on a Nicolet model impact 400D FT-IR spectrometer
(KBr pellets). Specific rotations were recorded on a Rudolf Research
Autopol IV automatic polarimeter. NMR spectra were measured
on a Bruker AMX 400 MHz spectrometer. ES-MS spectra were
obtained from an ES-MS (HP 1100 series, MSD single quadrupole)
instrument. Elemental analyses were recorded using Perkin Elmer
Analyser and the samples were dried under vacuum before analysis.
The TLC analysis was carried out on precoated silica gel plates using
the solvent system ethyl acetate: hexane (35: 65 v/v). All the solvents
were freshly distilled prior to use.
Received 27 August 2007; accepted 23 December 2007
Paper 07/4808
doi: 10.3184/030823407X272985
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