Synthesis and properties of MIDA boronate containing aromatic amino acids: New peptide building blocks

Article abstract of DOI:10.1039/c0ob00847h

Herein, we report the synthesis of novel phenylalanine and tyrosine derivatives containing a N-methyliminodiacetic acid boronate group. These compounds can be prepared enantiomerically pure, they are stable to column chromatography and they can be stored

Full text of DOI:10.1039/c0ob00847h

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PAPER
Synthesis and properties of MIDA boronate containing aromatic amino acids:
New peptide building blocks†
Neil Colgin,a Tony Flinnb and Steven L. Cobb*a
Received 7th October 2010, Accepted 13th December 2010
DOI: 10.1039/c0ob00847h
Herein, we report the synthesis of novel phenylalanine and tyrosine derivatives containing a
N-methyliminodiacetic acid boronate group. These compounds can be prepared enantiomerically pure,
they are stable to column chromatography and they can be stored in air for two months without
degradation occurring. This new class of boronate containing aromatic amino acids has potential
applications in both peptide chemistry and natural product synthesis.
The most widely utilised approach to prepare biaryl amino acid
Introduction
motifs involves a Suzuki–Miyaura coupling strategy.5 This ap-
In recent years naturally occurring peptides have become increas-
proach requires the preparation of the boron containing aromatic
ingly investigated as drug candidates in a range of diseases.1
amino acids. Such building blocks are typically obtained from the
However, the successful development of these peptide-based drugs
corresponding iodinated amino acids using Miyaura’s palladium
catalysed borylation (Scheme 1).6,7
relies on having synthetic access to both naturally occurring amino
acids and also a diverse tool-box of novel non-proteinogenic
amino acids. Within this area, amino acids that contain a biaryl
structural motif such as the biphenylalanines2 and dityrosine3 have
attracted considerable attention. This interest has largely been
stimulated by the fact that similar biaryl motifs are found in a
range of important naturally occurring cyclic peptides,4 including
the antibiotics Vancomycin and Biphenomycin B.
Scheme 1 Miyaura borylation of iodinated aromatic amino acids.
However, issues regarding the compatibility of the reaction
conditions required for Miyaura’s borylation and amino acid
chemistry have been reported. For example, racemisation of
the a-carbon has been documented for both iodophenylalanine
and iodotyrosine amino acid substrates.8 Furthermore, some
arylpinacolboronates (Bpin) including borylated tyrosine deriva-
tives produced in this reaction have been shown to be difficult to
purify and prone to degradation on silica gel.7b,8a,9
Herein, we report the synthesis of novel phenylalanine and tyro-
sine derivatives containing a N-methyliminodiacetic acid (MIDA)
boronate group (Fig. 1). These compounds can be prepared
enantiomerically pure, they are stable to column chromatography
aDepartment of Chemistry, Durham University, South Road, Durham, DH1
3LE, United Kingdom. E-mail: s.l.cobb@durham.ac.uk; Fax: +44 191 334
2051
bOnyx Scientific Limited, Silverbriar, Enterprise Park East, Sunderland,
SR5 2TQ, United Kingdom
† Electronic supplementary information (ESI) available: NMR spectra and
chiral HPLC analysis. See DOI: 10.1039/c0ob00847h
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Scheme 3 Synthesis of MIDA boronate 7. Reagents and conditions:
Boronic acid (8) (1.0 equiv.), N-methyl aminodiacetic acid (1.2 equiv.),
toluene: DMSO (15 : 1), D, 6 h, 81%. DMSO = dimethylsulfoxide.
Fig. 1 Novel amino acid MIDA boronates prepared in this study.
aromatic and heteroaromatic boronic acids are commercially
available meaning that one has ready access to a considerable
variety of MIDA protected coupling partners for the Negishi cross-
coupling outlined in Scheme 2.
and they can be stored in air for two months without degradation
occurring.
We envisaged that the boronates 1–3 could be accessed from
the orthogonally protected iodoalanine10 4 using established
palladium catalysed Negishi cross-coupling chemistry as shown
in Scheme 2.11 We postulated that the MIDA protecting group
developed by Burke12 would offer advantages over the Bpin
protecting group that is currently utilised in the preparation of
boronate containing aromatic amino acids. Although the MIDA
protecting group has already been shown to be highly stable
to a wide variety of synthetic reagents,12c its application in the
preparation of boronate containing amino acids has not been
exploited until now.
The palladium catalysed Negishi cross-coupling of protected
iodoalanines with aromatic halides has been investigated previ-
ously by Jackson.11 This methodology was appealing to us as
the reaction has been shown to proceed without racemisation
of the a-carbon of the amino acid. After minor modification
of Jackson’s original cross-coupling conditions14 we were able
to obtain both stereoisomers of compounds 1–3 in good yields
(Table 1). All of the products were purified on silica gel without
witnessing any protodeborylation. It is noteworthy that 3a and
3b were found to be stable to column chromatography given the
problems previously reported for the analagous Bpin boronates.8a,9
In addition, under the anhydrous base-free conditions utilised the
MIDA functionality remained intact. These results supported our
initial hypothesis that the MIDA protecting group represents a
Table 1 Synthesis of amino acid MIDA boronates 1–3
Scheme 2 General synthetic strategy.
Iodoalanine (4) Aromatic MIDA Product
Entry (stereochemistry) Boronate
(stereochemistry) Yield (%)a
Results and Discussion
1
2
3
4
5
6
S
R
S
R
S
R
5
5
6
6
7
7
1a (S)
1b (R)
2a (S)
2b (R)
3a (S)
3b (R)
65
62
58
59
61
59
Two of the MIDA boronates required (5 and 6) were purchased
commercially, however in theory these can also be easily prepared
from the corresponding boronic acids using the MIDA protection
conditions developed by Burke et al.13 To illustrate this point,
the MIDA boronate 7 which is not commercially available was
readily synthesised in excellent yield from the available boronic
acid 8 (Scheme 3). It is worth noting that a range of iodo/bromo
a Isolated yield given.
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Table 2 Synthesis of biaryl amino acids 9–11
Both stereoisomers of the biaryl amino acids 9–11 were
prepared in good yields using unoptimised reaction conditions.15
Chiral HPLC analysis of the products confirmed that the initial
stereochemistry of the iodoalanines 4a and 4b used had remained
intact through both the Negishi coupling used to prepare the
amino acid MIDA boronates 1–3 and the subsequent Suzuki–
Miyaura cross-coupling.16
MIDA boronates have previously been reported to exhibit
stability to long term benchtop storage.12 This is one of the major
advantages that the MIDA protecting group offers in terms of
the preparation of useful synthetic building blocks. To confirm
that the MIDA boronates prepared in this study display similar
properties, 1–3 were left exposed to air at room temperature for a
period of 2 months. 1H NMR and TLC analysis after this period
indicated that no detectable degradation of 1–3 had occurred. In
addition we repeated the synthesis of the biaryl amino acids 9–
11 using identical Suzuki–Miyaura coupling conditions to those
given in Table 2. The isolated yields recorded for the biaryl amino
acids this time were comparable to those previously obtained (see
Table 2).
Having investigated the stability of the amino acid MIDA
boronates we next turned our attention to confirming that; a)
the orthogonal protecting groups could be selectivity cleaved and
b) the MIDA group was stable to standard peptide coupling
conditions.17 Both of these properties are essential for new peptide
building blocks to be of synthetic use. To investigate a) and b)
we prepared two test dipeptides. Cleavage of the benzyl ester
from 1a was readily achieved through hydrogenolysis without
affecting the MIDA ester functionality (Scheme 4). Amino acid
12 was then coupled to commercially available NH2-Ala-OMe
to give the dipeptide 13. This conversion was achieved using
Amino acid MIDA
Boronate
Entry (Stereochem.)
Biaryl
Amino acid
Yield
(%)a
Yield
(%)a,c
ee (%)b
1
2
3
4
5
6
1a (S)
1b (R)
2a (S)
2b (R)
3a (S)
3b (R)
9a
9b
10a
10b
11a
11b
63
65
62
57
57
58
99.0
97.4
99.0
99.0
99.6
99.6
65
67
64
59
58
62
R
PyBOPꢀ mediated peptide coupling conditions. This synthetic
a Isolated yield given. b Enantiomeric excess (ee) was determined by chiral
HPLC. c Amino acid MIDA boronates used were stored at RT for 2
months.
step proceeded in excellent yield and the MIDA protecting group
remained intact.
good alternative to the Bpin group for the preparation of boronate
containing amino acids.
Compounds 1–3 can be used as synthetic building blocks to
prepare various peptide biaryl motifs using Suzuki–Miyaura cross-
coupling reactions. However, if 1–3 are used as coupling partners in
this type of reaction the MIDA protecting group must be removed
using a mild aqueous base prior to coupling. In theory, the use
of a mild base in this hydrolysis step has the potential to cause
racemisation of the a-carbon of the amino acid. Thus, in order to
both confirm the enantiomeric purity of the amino acid MIDA
boronates prepared (1–3) and to investigate their compatibility
with Suzuki–Miyaura reaction conditions we decided to prepare
the corresponding biaryl amino acids 9–11.
The biaryl amino acids were prepared using the Suzuki–
Miyaura conditions given by Knapp et al.12a in which the boronic
acid is de-masked in situ by hydrolysis of the MIDA boronate.
A trial hydrolysis reaction was first performed using the simple
MIDA boronate 7. Stirring at 50 ◦C for 2 h with 3.0 equiv.
of K3PO4 afforded >90% of the desired free boronic acid 8 (as
determined by 1H NMR). We then proceeded to perform the
Suzuki–Miyaura cross-coupling reactions with boronates 1–3 and
iodobenzene (Table 2).
Scheme
4
Synthesis of MIDA boronate containing dipeptide 13.
Reagents and conditions: (a) 10% Pd/carbon, MeOH, RT, 2 h, 86% (b)
NH2-Ala-OMe, NMM, PyBOPꢀR , RT, 15 h, 82%.
Having established that the benzyl ester could be selectively
cleaved, a second dipeptide, accessed via the Boc protected
nitrogen of 1a was prepared. The Boc protecting group was
removed using trifluoroacetic acid/dichloromethane to give the
salt 14. The TFA salt 14 was not isolated but reacted immediately
R
with Boc-Ala-OH under PyBOPꢀ amide coupling conditions to
give dipeptide 15 in a 52% yield over two steps (Scheme 5). The
1866 | Org. Biomol. Chem., 2011, 9, 1864–1870
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afluorophosphate. ‘SPhos’ refers to 2-dicyclohexylphosphino-
2¢,6¢-dimethoxybiphenyl. Melting points were recorded on a
Gallenkamp melting point apparatus and are uncorrected. IR
spectra were recorded on a Perkin Elmer Spectrum RX1 fitted with
an ATR attachment. High resolution mass spectra were collected
on a Waters Acquity LCT Premier XE. Enantiomeric excess (ee)
was determined by HPLC and was performed by Onyx Scientific
Ltd using an Agilent 1100 series. LC conditions: Chiralpak IA
5 mM 4.6 ¥ 250 mm (220 nm); Mobile Phase: hexane:IPA (60 : 40);
Flow rate: 1.0 mL min-1; 5 mL injection. Optical rotations were
measured with a Jasco P-1020 polarimeter.
2-(5-bromo-2-methoxyphenyl)-6-methyl-1,3,6,2-dioxazaborocane-
4,8-dione 7
Scheme
5
Synthesis of MIDA boronate containing dipeptide 15.
Reagents and conditions: (a) TFA : DCM (1 : 1), RT, 5 h (b) Boc-Ala-OH,
5-Bromo-2-methoxyphenyl boronic acid 8 (1.5 g, 6.5 mmol) and
N-methyl iminodiacetic acid (1.2 g, 8.0 mmol) were dissolved in
toluene (120 mL) and DMSO (8 mL) and heated at reflux (Dean–
Stark apparatus) for 6 h. The solution was allowed to return to
room temperature and the resulting precipitate filtered, washed
with water (20 mL) followed by ether (40 mL) and oven dried to
give the desired product 7 as a white solid* (1.8 g, 81%). m.p.:
276.2–275.4 ◦C; nmax/cm-1 3025, 2963, 2919, 2831, 1746, 1588,
1460, 1383, 1332, 1292, 1236, 1179, 1029, 1000, 902, 866, 800, 708,
653, 621; dH (400 MHz, CD3CN) 2.63 (3 H, s, NCH3), 3.75 (3
H, s, OCH3), 3.95 (2 H, d, J 17.2 Hz, 2 ¥ CHa), 4.08 (2 H, d,
J 17.2 Hz, 2 ¥ CHb), 6.89 (1 H, d, J 8.8 Hz, ArH), 7.51 (1 H,
dd, J 8.8 and 2.4 Hz, ArH), 7.62 (1 H, br s, ArH); dC (100 MHz,
CD3CN) 46.7, 54.8, 63.2, 112.1, 112.6, 112.6, 132. 9, 136.5, 161.2,
NMM, PyBOPꢀR , RT, 15 h, 52% (two steps). TFA = trifluoroacetic acid.
MIDA protecting group was again found to be compatible with
the reaction conditions used.
Conclusion
In summary, we have prepared three novel MIDA boronate
containing aromatic amino acids 1–3 via a Negishi cross-coupling
between an orthogonally protected iodoalanine and aromatic
MIDA boronates. In the preparation of 1–3 no racemisation of
the amino acid a-carbon was observed and column purification
on silica gel was possible. Therefore, this methodology offers an
alternative approach to access protected amino acid boronates
in cases where the Bpin protecting group has been found to be
unsuitable. Furthermore, we have shown that 1–3 are benchtop
stable and that the MIDA functionality is compatible with reaction
conditions of importance in peptide chemistry. We are currently
in the process of investigating the further applications of 1–3 as
building blocks in the preparation of biaryl containing peptide
natural products.
168.2; dB (128 MHz, CD3CN) 11.1; m/z (AP) 340.0093 (M+
+
Na. C12H13BBrNO5 requires 340.0106). *This compound may
be purified via column chromatography if required (SiO2, 100%
EtOAc).
General Procedure for the Synthesis of Amino Acid MIDA
Boronates 1–3
Zinc dust (0.31 g, 4.8 mmol) was placed in a 2-necked round
bottomed flask fitted with a thermometer and septum. The flask
was evacuated under heating for 15 min. with vigorous stirring.
After cooling to room temperature under argon, anhydrous DMF
(1 mL) and I2 (10 mg) were added and the light grey suspension
stirred for 5 min. followed by the addition of (S)-iodoalanine
4a or (R)-iodoalanine 4b (0.50 g, 1.2 mmol) in DMF (1 mL)
[exotherm]. Upon returning to room temperature Pd(dba)2 (21 mg,
3 mol.%), P(o-tol)3 (33 mg, 9 mol.%) and the relevant halogenated
MIDA boronate 5, 6 or 7 (1.14 mmol) were added as solids
and the resulting black mixture stirred at 50 ◦C under argon
for 6 h. After cooling to room temperature the reaction mixture
was purified via column chromatography without work-up (SiO2;
50/50 hexane/EtOAc → 100% EtOAc) to furnish the desired
products as white or pale yellow solids.
Experimental Section
General
NMR spectra were collected using a Bruker Avance 400 MHz,
Varian Inova 500 MHz and a Varian VNMRS 700 MHz.
multiplicities; s = singlet, d = doublet, dd = doublet of doublets,
m = multiplet, t = triplet, q = quartet, bd = broad doublet, bs =
broad singlet). Chemical shifts are reported in d units and are
referenced to residual solvent peaks; CHCl3 (1H 7.26 ppm, 13C
77.0 ppm), CH3CN (1H 1.94 ppm, 13C 1.3 ppm) and DMSO (1H
2.50 ppm, 13C 39.5 ppm). All reactions were monitored by TLC
using Merck precoated silica gel plates. Column chromatography
was performed using silica gel (40–60 mM) using the solvent
indicated. All reported yields refer to the isolated yield unless
otherwise indicated and product purity was estimated to be >
95% by 1H-NMR. (R) and (S)-iodoalanines were obtained as gifts
(S)-benzyl 2-(tert-butoxycarbonylamino)-3-(4-(6-methyl-4,8-
dioxo-1,3,6,2-dioxazaborocan-2-yl)phenyl)propanoate 1a
R
from Onyx Scientific Ltd, Sunderland. PyBOPꢀ was purchased
from CEM Peptides. All other chemicals were purchased from
Sigma Aldrich or Alfa Aesar and were used without further
(0.375 g, 65%) from 0.409 g of 4-iodophenyl boronic acid MIDA
ester 5. m.p.: 105.2–106.6 ◦C; [a]D = -10.7 (c 0.5 in MeOH);
24
R
purification. ‘NMM’ refers to N-methylmorpholine. ‘PyBOPꢀ’
n
max/cm-1 2950, 2924, 2844, 1743, 1688, 1499, 1454, 1336, 1230,
refers to (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hex-
1162, 1038, 990, 864, 752; dH (400 MHz, CDCl3) 1.41 (9 H, s, tBu),
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2.48 (3 H, s, NCH3), 3.02–3.14 (2 H, m, CH2), 3.73 (2 H, dd, J
16.4 and 3.2 Hz, 2 ¥ CHa), 3.90 (2 H, br d, J 16.4 Hz, 2 ¥ CHb),
4.60–4.63 (1 H, m, CH), 5.01 (1 H, br d, J 8.4 Hz, NH), 5.08–5.16
(2 H, m, CH2), 7.09 (2 H, d, J 7.6 Hz, ArH), 7.27–7.30 (2 H, m,
ArH), 7.34–7.39 (5 H, m, ArH); dC (100 MHz, CDCl3) 28.3, 38.3,
47.6, 54.6, 61.8, 67.2, 80.0, 128.4, 128.5, 128.6, 128.9, 129.4, 132.5,
135.2, 137.8, 155.1, 168.2, 171.7; dB (128 MHz, CDCl3) 12.0; m/z
(ESI) 532.2102 (M+ + Na. C26H31BN2O8 requires 532.2107).
(S)-enantiomer 2a; m/z (ESI) 532.2092 (M+ + Na. C26H31BN2O8
requires 532.2107).
(R)-benzyl-2-(tert-butoxycarbonylamino)-3-(4-methoxy-3-(6-
methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)phenyl)propanoate
3b
(0.360 g, 59%) from 0.390 g of 2-(5-bromo-2-methoxyphenyl)-6-
24
methyl-1,3,6,2-dioxazaborocane-4,8-dione 7. [a]D = +9.9 (c 0.5 in
MeOH); nmax/cm-1 2968, 1756, 1746, 1708, 1489, 1455, 1338, 1289,
1237, 1166, 1028, 868, 751, 700, 656. 1H, 13C and 11B NMR data
correspond to that of the (S)-enantiomer 3a; m/z (ESI) 562.2210
(M+ + Na. C27H33BN2O9 requires 562.2213).
(S)-benzyl 2-(tert-butoxycarbonylamino)-3-(3-(6-methyl-4,8-
dioxo-1,3,6,2-dioxazaborocan-2-yl)phenyl)propanoate 2a
(0.583 g, 58%) from 0.670 g of 3-iodophenyl boronic acid MIDA
ester 6. m.p.: 108.0–109.9 ◦C; [a]D = -11.4 (c 0.4 in MeOH);
24
max/cm-1 2963, 2913, 1750, 1742, 1704, 1499, 1455, 1337, 1252,
General Procedure for the Synthesis of Biphenyalanines 9–11
n
1166, 1037, 969, 864, 791, 753, 699; dH (400 MHz, CDCl3) 1.37 (9
H, s, tBu), 2.42 (3 H, s, NCH3), 2.99 (1 H, dd, J 14.0 and 7.6 Hz,
CHa), 3.14 (1 H, dd, J 14.0 and 6.4 Hz, CHb), 3.76 (2 H, dd, J
16.0 and 8.4 Hz, 2 ¥ CHa), 3.89 (2 H, br d, J 16.0 Hz, 2 ¥ CHb),
4.59–4.61 (1 H, m, CH), 4.96 (1 H, br d, J 6.4 Hz, NH), 5.09–5.19
(2 H, m, CH2), 7.12 (1 H, d, J 6.8 Hz, ArH), 7.26–7.41 (8 H,
m, ArH); dC (100 MHz, CDCl3) 28.3, 38.4, 47.7, 54.8, 61.9, 67.1,
80.4, 128.4, 128.5, 128.6, 128.6, 130.8, 130.9, 133.2, 135.0, 135.3,
136.0, 155.1, 169.0, 172.0; dB (128 MHz, CDCl3) 11.5; m/z (ESI)
532.2111 (M+ + Na. C26H31BN2O8 requires 532.2107).
The relevant boronic acid MIDA ester (0.3 mmol), Pd(OAc)2
(1.7 mg, 2.5 mol.%), SPhos (6.2 mg, 5.0 mol.%), K3PO4 (0.22 g,
1.05 mmol) and iodobenzene (0.05 mL, 0.45 mmol) were dissolved
in a degassed mixture of 1,4-dioxane/H2O (1.8/0.18 mL) under
argon. The resulting black solution was stirred at 70 ◦C for
48 h. Upon cooling the reaction mixture was purified via column
chromatography without work-up (SiO2, 100% hexane; 85%
hexane/15% diethyl ether) to give the products as white or tan
solids.
(S)-benzyl 3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)-
propanoate 9a
(S)-benzyl 2-(tert-butoxycarbonylamino)-3-(4-methoxy-3-(6-me-
thyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)phenyl)propanoate 3a
(82 mg, 63%) from 0.150 g of boronic acid MIDA ester 1a. m.p.:
96.3 ◦C; [a]D = -10.8 (c 0.5 in MeOH) (99.0% ee); nmax/cm-1 2988,
(0.190 g, 61%) from 0.198 g of 2-(5-bromo-2-methoxyphenyl)-
24
6-methyl-1,3,6,2-dioxazaborocane-4,8-dione 7. m.p.: 116.6–
2913, 2838, 1738, 1686, 1519, 1490, 1298, 1248, 1151, 1022, 1006,
761, 738, 694; dH (400 MHz, CDCl3) 1.42 (9 H, s, tBu), 3.09–3.17
(2 H, m, CH2), 4.64–4.69 (1 H, m, CH), 5.02 (1 H, br d, J 8.4 Hz,
NH), 5.10–5.21 (2 H, m, CH2), 7.11 (2 H, d, J 8.0 Hz, ArH), 7.28–
7.30 (2 H, m, ArH), 7.32–7.36 (4 H, m, ArH), 7.42–7.45 (4 H, m,
ArH), 7.54–7.57 (2 H, m, ArH); dC (100 MHz, CDCl3) 28.3, 38.0,
54.5, 67.2, 80.0, 127.0, 127.0, 127.2, 128.5, 128.5, 128.6, 128.7,
129.8, 135.0, 135.2, 139.9, 140.8, 155.1, 171.7; m/z (ESI) 454.1999
(M+ + Na. C27H29NO4 requires 454.1994).
◦
117.3 C. [a]D = -10.0 (c 0.5 in MeOH); nmax/cm-1 2956, 1750,
24
1746, 1700, 1489, 1454, 1338, 1290, 1237, 1167, 1029, 867, 820,
t
752, 700, 656. dH (400 MHz, CDCl3) 1.40 (9 H, s, Bu), 2.59 (3
H, s, NCH3), 3.00–3.08 (2 H, m, CH2), 3.77 (3 H, s, OCH3),
3.91–3.96 (4 H, m, 2 ¥ CH2), 4.54–4.60 (1 H, m, CH), 4.96 (1
H, br d, J 7.6 Hz, NH), 5.10–5.17 (2 H, m, CH2), 6.77 (1 H, d,
J 8.4 Hz, ArH), 7.08 (1 H, dd, J 8.4 and 2.0 Hz, ArH), 7.33–
7.38 (5 H, m, ArH), 7.43 (1 H, d, J 2.0 Hz, ArH); dC (100 MHz,
CDCl3) 28.3, 37.6, 47.5, 55.5, 63.7, 67.1, 79.9, 110.6, 128.4, 128.5,
128.6, 132.1, 133.9, 135.3, 135.8, 135.8, 137.4, 155.1, 161.3, 168.3,
171.9; dB (128 MHz, CDCl3) 10.5; m/z (ESI) 562.2224 (M+ + Na.
C27H33BN2O9 requires 562.2213).
(S)-benzyl 3-(biphenyl-3-yl)-2-(tert-butoxycarbonylamino)-
propanoate 10a
(81 mg, 62%) from 0.150 g of boronic acid MIDA ester 2a. m.p.:
99.3 ◦C; [a]D = -10.6 (c 0.5, MeOH) (99.0% ee); nmax/cm-1 2920,
24
(R)-benzyl 2-(tert-butoxycarbonylamino)-3-(4-(6-methyl-4,8-
2831, 1729, 1689, 1518, 1455, 1369, 1262, 1164, 1054, 1029, 978,
899, 754, 702; dH (400 MHz, CDCl3) 1.41 (9 H, s, tBu), 3.11–3.22
(2 H, m, CH2), 4.66–4.71 (1 H, m, CH), 5.01–5.04 (1 H, br d, J
8.4 Hz, NH), 5.09–5.17 (2 H, m, CH2), 7.02 (1 H, d, J 8.0 Hz,
ArH), 7.24–7.37 (8 H, m, ArH), 7.41–7.47 (3 H, m, ArH), 7.52–
7.55 (2 H, m, ArH); dC (100 MHz, CDCl3) 28.3, 38.3, 54.5, 67.2,
80.0, 125.9, 127.2, 127.2, 127.3, 128.2, 128.3, 128.4, 128.6, 128.7,
128.9, 135.2, 136.4, 141.0, 141.5, 155.1, 171.7; m/z (ESI) 454.1980
(M+ + Na. C27H29NO4 requires 454.1994).
dioxo-1,3,6,2-dioxazaborocan-2-yl)phenyl)propanoate 1b
(0.358 g, 62%) from 0.409 g of 4-iodophenyl boronic acid MIDA
ester 5. [a]D = +10.0 (c 0.5 in MeOH); nmax/cm-1 2969, 1742, 1690,
24
1500, 1454, 1336, 1230, 1162, 1038, 991, 862, 753, 699. 1H, 13C and
11B NMR data correspond to that of the (S)-enantiomer 1a; m/z
(ESI) 532.2117 (M+ + Na. C26H31BN2O8 requires 532.2107).
(R)-benzyl 2-(tert-butoxycarbonylamino)-3-(3-(6-methyl-4,8-
dioxo-1,3,6,2-dioxazaborocan-2-yl)phenyl)propanoate 2b
(S)-benzyl 2-(tert-butoxycarbonylamino)-3-(6-methoxybiphenyl-3-
yl)propanoate 11a
(0.562 g, 59%) from 0.671 g of 3-iodophenyl boronic acid MIDA
ester 6. [a]D = +11.6 (c 0.5 in MeOH); nmax/cm-1 2879, 1756,
24
1742, 1704, 1499, 1454, 1336, 1251, 1166, 1038, 988, 891, 862, 788,
(79 mg, 57%) from 0.162 g of boronic acid MIDA ester 3a. m.p.:
130.6 - 130.8 ◦C; [a]D = -9.8 (c 0.5 in MeOH) (99.6% ee);
1
24
738, 699. H, 13C and 11B NMR data correspond to that of the
1868 | Org. Biomol. Chem., 2011, 9, 1864–1870
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n
max/cm-1 2950, 2924, 2851, 1725, 1702, 1504, 1489, 1444, 1366,
132.2, 134.0, 138.7, 155.4, 169.4, 173.6; dB (128 MHz, DMSO-d6)
10.6; m/z (ESI) 419.1640 (M–H. C19H25BN2O8 requires 419.1626).
1240, 1208, 1154, 1030, 1012, 962, 865, 759, 730, 702; dH (400 MHz,
CDCl3) 1.41 (9 H, s, tBu), 3.02–3.12 (2 H, m, CH2), 3.78 (3 H, s,
OMe), 4.60–4.65 (1 H, m, CH), 5.02 (1 H, br d, J 7.6 Hz, NH),
5.09–5.17 (2 H, m, CH2), 6.83 (1 H, d, J 8.0 Hz, ArH), 6.98 (1
H, d, J 8.0 Hz, ArH), 7.04 (1 H, br s, ArH), 7.27–7.49 (10 H,
m, ArH); dC (100 MHz, CDCl3) 28.3, 37.4, 54.6, 55.6, 67.1, 80.0,
111.4, 127.0, 128.0, 128.0, 128.4, 128.6, 129.3, 129.5, 130.4, 132.0,
135.2, 135.2, 138.3, 155.1, 155.6, 171.8; m/z (ESI) 484.2093 (M+ +
Na. C28H31NO5 requires 484.2100).
(S)-methyl-2-((S)-2-(tert-butoxycarbonylamino)-3-(4-(6-methyl-
4,8-dioxo-1,3,6,2 dioxazaborocan-2-yl)phenyl)-
propanamido)propanoate 13
NMM (0.1 mL, 0.9 mmol) was added to a solution of NH2-Ala-
OMe. HCl (38 mg, 0.3 mmol) in DCM (2 mL) and the mixture
stirred at room temperature for 5 min. followed by the addition of
R
PyBOPꢀ (155 mg, 0.3 mmol) and 12 (125 mg, 0.3 mmol) in DCM
(1 mL). The resulting pale yellow solution was stirred at room
temperature for 15 h. The volatiles were removed in vacuo to give a
yellow oil which was purified via column chromatography (50/50
(R)-benzyl 3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)-
propanoate 9b
(85 mg, 65%) from 0.150 g of boronic acid MIDA ester 1b.
EtOAc/Hexane →100% EtOAc) to afford the desired product 13
[a]D = +11.7 (c 0.3 in MeOH) (97.4% ee); nmax/cm-1 2931, 2979,
as a white solid (120 mg, 82%). m.p.: 130.5–131.9 ◦C. [a]D
=
24
24
1728, 1689, 1518, 1455, 1368, 1260, 1164, 1054, 1028, 978, 754,
698, 662.1H and 13C NMR data correspond to that of the (S)-
enantiomer 9a. m/z (ESI) 454.1977 (M+ + Na. C27H29NO4 requires
454.1994).
-10.1 (c 1.0 in CH3CN); nmax/cm-1 2926, 1742, 1660, 1514, 1454,
1367, 1338, 1229, 1161, 1039, 991, 837; dH (500 MHz, CD3CN)
1.32 (12 H, br s, tBu), 2.48 (3 H, s, NCH3), 2.81 (1 H, dd, J 13.5
and 9.5 Hz, 1 ¥ CHa), 3.11 (1 H, dd, J 13.5 and 4.0 Hz, 1 ¥ CHb),
3.66 (3 H, s, OCH3), 3.88 (2 H, dd, J 17.0 and 4.0 Hz, 2 ¥ CHa),
4.06 (2 H, dd, J 17.0 and 2.0 Hz, 2 ¥ CHb), 4.27–4.32 (1 H, m,
CH), 4.36–4.41 (1 H, m, CH), 5.56 (1 H, br d, J 8.0 Hz, NH), 7.04
(1 H, br d, J 6.5 Hz, NH), 7.25 (2 H, d, J 7.5 Hz, ArH), 7.42 (2 H,
d, J 7.5 Hz, ArH); dC (125 MHz, CD3CN) 18.5, 29.1, 39.4, 49.1,
49.6, 53.5, 57.1, 63.4, 80.6, 130.6, 134.1, 140.3, 157.0, 170.3, 173.0,
174.5; dB (128 MHz, CD3CN) 11.0; m/z (ESI) 527.2156 (M+ + Na.
C23H32BN3O9 requires 527.2166).
(R)-benzyl 3-(biphenyl-3-yl)-2-(tert-butoxy-
carbonylamino)propanoate 10b
24
(74 mg, 57%) from 0.150 g of boronic acid MIDA ester 2b. [a]D
=
+10.6 (c 0.5 in MeOH) (99.0% ee); nmax/cm-1 2978, 2913, 1749,
1697, 1514, 1456, 1160, 1060, 898, 869, 758, 698.1H and 13C NMR
data correspond to that of the (S)-enantiomer 10a. m/z (ESI)
454.1996 (M+ + Na. C27H29NO4 requires 454.1994).
(S)-methyl 2-((S)-2-(tert-butoxycarbonylamino)-3-(4-(6-
methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-
yl)phenyl)propanamido)propanoate 15
(R)-benzyl 2-(tert-butoxycarbonylamino)-3-(6-methoxybiphenyl-3-
yl)propanoate 11b
24
(80 mg, 58%) from 0.162 g of boronic acid MIDA ester 3b. [a]D
=
TFA (2 mL) was added to a stirred solution of 1a (65 mg, 0.13
mmol) in DCM (2 mL) at room temperature and the resulting
pale yellow solution stirred for 5 h. The volatiles were removed
under reduced pressure and residual TFA was removed by co-
evaporation with ether (x 4). The crude material 14 was taken up
in DCM (1 mL), NMM (0.04 mL, 0.38 mmol) was added and the
solution stirred at room temperature for 5 min. followed by the
+9.9 (c 0.3 in MeOH) (99.6% ee); nmax/cm-1 2927, 2831, 1729, 1689,
1518, 1454, 1369, 1261, 1164, 1054, 1028, 978, 801, 754, 702, 662.
1H and 13C NMR data correspond to that of the (S) enantiomer
11a. m/z (ESI) 484.2091 (M+ + Na. C28H31NO5 484.2100).
(S)-2-(tert-butoxycarbonylamino)-3-(4-(6-methyl-4,8-dioxo-
1,3,6,2-dioxazaborocan-2-nyl)phenyl)propanoic acid 12
R
addition of PyBOPꢀ (66 mg, 0.13 mmol) and Boc-Ala-OH (24 mg,
0.13 mmol) in DCM (1 mL). After stirring at room temperature
for 12 h the volatiles were removed under reduced pressure and
purification via column chromatography (50/50 EtOAc/hexane
→100% EtOAc) afforded the title compound 15 as a white solid
(S)-benzyl-2-(tert-butoxycarbonylamino)-3-(4-(6-methyl-4,8-
dioxo-1,3,6,2-dioxazaborocan-2-yl)phenyl)propanoate
1a
(0.284 g, 0.56 mmol) was added to a suspension of 10% Pd/C
(57 mg, 10% wt.) (50% wet) in MeOH (8 mL) at room temperature
and the reaction mixture was stirred under an atmosphere of H2
for 2 h. The reaction mixture was filtered though a plug of celite,
washing with MeOH (5 mL) and the volatiles removed in vacuo
to give to desired product 12 as a white solid (0.20 g, 86%) which
was used without further purification (NMR indicated purity of
(38 mg, 52%). m.p.: 131.2–132.0 ◦C. [a]D = -9.9 (c 1.0 in CH3CN);
24
n
max/cm-1 2938, 1742, 1680, 1518, 1455, 1369, 1343, 1252, 1191,
1042, 995, 833, 741, 700; dH (700 MHz, CD3CN) 1.17 (3 H, d,
J 7.0 Hz, CH3), 1.39 (9 H, s, Bu), 2.44 (3 H, s, NCH3), 3.03 (1
t
H, dd, J 13.3 and 7.0 Hz, 1 ¥ CHa), 3.13 (1 H, dd, J 14.0 and
5.6 Hz, 1 ¥ CHb), 3.86 (2 H, dd, J 17.5 and 3.5 Hz, 2 ¥ CHa),
4.00 (1 H, br s, CH), 4.06 (2 H, d, J 17.5 Hz, 2 ¥ CHb), 4.68 (1
H, dd, J 13.3 and 7.0 Hz, CH), 5.07–5.11 (2 H, m, CH2), 5.54–
5.55 (1 H, m, NH), 6.93 (1 H, br s, NH), 7.18 (2 H, d, J 7.7 Hz,
ArH), 7.30–7.32 (2 H, m, ArH), 7.33–7.39 (5 H, m, ArH); dC
(175 MHz, CD3CN): d 18.4, 28.5, 38.1, 48.4, 50.9, 54.4, 62.7, 67.5,
79.9, 129.1, 129.1, 129.4, 129.9, 133.5, 136.7, 138.7, 156.3, 169.5,
172.1, 173.6; dB (128 MHz, CD3CN) 11.3; m/z (ESI) 603.2468
(M+ + Na. C29H36BN3O9 requires 603.2479).
greater than 90%). [a]D = +24.8 (c 0.3 in MeOH); nmax/cm-1
24
2958, 2906, 1742, 1688, 1514, 1454, 1368, 1337, 1229, 1162, 1038,
992, 889, 863, 816, 710; dH (400 MHz, DMSO-d6) 1.31 (9 H, s,
tBu), 2.47 (3 H, s, NCH3), 2.82 (1 H, m, 1 ¥ CHa), 3.01 (1 H,
dd, J 13.6 and 3.6 Hz, 1 ¥ CHb), 4.09–4.14 (3 H, m, CH and 2 ¥
CHa), 4.31 (2 H, d, J 17.2 Hz, 2 ¥ CHb), 7.09 (1 H, d, J 8.4 Hz,
NH), 7.23 (2 H, d, J 7.6 Hz, ArH), 7.34 (2 H, d, J 7.6 Hz, ArH);
dC (100 MHz, DMSO-d6) 28.1, 36.4, 47.5, 55.0, 61.7, 78.0, 128.4,
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8 (a) M. Prieto, S. Mayor, P. Llyod-Williams and E. Giralt, J. Org. Chem.,
2009, 74, 9202–9205; (b) P. Capek, R. Pohl and M. Hocek, J. Org.
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Acknowledgements
ˇ
We thank the Ramsay Memorial Trust (SLC) and One North
East and HEFCE for a Durham Bridging Fellowship (NC). We
are also grateful to Katie Poole (Onyx Scientific Limited) for
their invaluable assistance in the chiral analysis of compounds
prepared and to Onyx Scientific Limited for the gift of the
iodoalanines (4).
9 T. C. Roberts, P. A. Smith, R. T. Cirz and F. E. Romesberg, J. Am.
Chem. Soc., 2007, 129, 15830–15838.
10 The iodoalanines used in this study were prepared on a multi-gram scale
using literature procedures; R. F. W. Jackson, J. Org. Chem., 1992, 57,
3397–3404.
11 (a) A. J. Ross, H. L. Lang and R. F. W. Jackson, J. Org. Chem., 2010,
75, 245–248; (b) C. L. Oswald, T. Carrillo-Marquez, L. Caggiano and
R. F. W. Jackson, Tetrahedron, 2008, 64, 681–687; (c) R. F. W. Jackson,
R. J. Moore, C. S. Dexter, J. Elliot and C. E. Mowbray, J. Org. Chem.,
1998, 63, 7875–7884; (d) C. S. Dexter, C. Hunter, R. F. W. Jackson
and J. Elliott, J. Org. Chem., 2000, 65, 7417–7421; (e) C. Malan and C.
Morin, Synlett, 1996, 167.
12 (a) D. M. Knapp, E. P. Gillis and M. D. Burke, J. Am. Chem. Soc., 2009,
131, 6961–6963; (b) E. P. Gillis and M. D. Burke, J. Am. Chem. Soc.,
2007, 129, 6716–6717; (c) E. P. Gillis and M. D. Burke, Aldrichimica
Acta, 2009, 42, 17–27.
13 E. P. Gillis and M. D. Burke, J. Am. Chem. Soc., 2008, 130, 14084–
14085.
14 In our hands we found that Negishi coupling reactions utilising only
4.0 equiv. of zinc compared to the 6.0 equiv. reported by Jackson
et al. (see ref. 10d) gave identical results. We also found that the less
expensive catalyst Pd(dba)2 could be used in place of Pd2(dba)3 but
gave comparable yields in this reaction.
15 A Pd(OAc)2 catalysis loading of 2.5 mol.% was utilised instead of
1.5 mol.% as this led to a slight increase in the reaction yields obtained.
Increasing the catalysis loading to 5.0 mol.% has been reported to
produced improve yields (see ref. 11a) but this was not investigated
as in our study the primary focus was on confirming stereochemical
integrity of the amino acids a-carbon.
16 We chose to use Buchwald coupling conditions (SPhos 5.0 mol.%)
as such conditions had previously been documented to help suppress
racemisation of the a-carbon on the amino acid (see ref. 8a).
17 The Bpin protecting group has previously been shown to be stable to
standard peptide coupling conditions for example see ref. 5b.
Notes and references
1 (a) P. Vlieghe, V. Lisowski, J. Martinez and M. Khrestchatisky, Drug
Discovery Today, 2010, 15, 40–56; (b) A. K. Sato, M. Viswanathan,
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642.
2 Y. Gong and W. He, Org. Lett., 2002, 4, 3803–3805.
3 (a) C. A. Hutton and O. Skaff, Tetrahedron Lett., 2003, 44, 4895–4898;
(b) E. Moreno, L. A. Nolasco, L. Caggiano and R. F. W. Jackson, Org.
Biomol. Chem., 2006, 4, 3639–3647.
4 For example see review: L. Feliu and M. Planas, Int. J. Pept. Res. Ther.,
2005, 11, 53–97.
5 (a) P. J. Krenitsky and D. L. Boger, Tetrahedron Lett., 2003, 44, 4019–
4022; (b) R. Le´pine and J. Zhu, Org. Lett., 2005, 7, 2981–2984; (c) P.
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Capek, R. Pohl and M. Hocek, Org. Biomol. Chem., 2006, 4, 2278–
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2284; (d) P. Capek, H. Cahova´, R. Pohl, M. Hocek, C. Gloeckner and
A. Marx, Chem.–Eur. J., 2007, 13, 6196–6203.
6 T. Ishiyama, M. Murata and N. Miyauara, J. Org. Chem., 1995, 60,
7508–7510.
7 (a) I. B. Sivaev and V. I. Bregadze, ARKIVOC, 2008, (iv), 47–61;
(b) Recently iridium-catalyzed borylation of protected amino acids via
direct C-H activation has also been reported; F.-M. Meyer, L. Spiros,
A. Guzman-Peres, C. Perreault, J. Bian and K. James, Org. Lett., 2010,
12, 3870–3873. However, this chemistry still gives rise to the production
of Bpin containing amino acids.
1870 | Org. Biomol. Chem., 2011, 9, 1864–1870
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The Royal Society of Chemistry 2011
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