Negishi cross-coupling reactions of α-amino acid-derived organozinc reagents and aromatic bromides

Article abstract of DOI:10.1016/j.tet.2007.11.031

The Negishi cross-coupling reaction of organozinc iodides derived from α-amino acids with aromatic bromides to give substituted phenylalanine derivatives is described, using either Pd(OAc)₂ or Pd₂(dba)₃ in combination with P(o-Tol)₃ as catalyst in DMF at 50 °C. Similar results are obtained using Pd[P^tBu₃]₂ as catalyst. The difference in reactivity displayed between aryl iodides and bromides (ArI>ArBr) has been utilised in a short synthesis of an unsymmetrical, orthogonally protected para-phenylene bis-alanine derivative.

Full text of DOI:10.1016/j.tet.2007.11.031

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 681e687
www.elsevier.com/locate/tet
Negishi cross-coupling reactions of a-amino acid-derived organozinc
reagents and aromatic bromides
,y
*
Claire L. Oswald, Tomas Carrillo-Marquez, Lorenzo Caggiano , Richard F.W. Jackson
*
´
´
Department of Chemistry, Dainton Building, The University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
Received 30 August 2007; received in revised form 21 October 2007; accepted 8 November 2007
Available online 12 November 2007
Abstract
The Negishi cross-coupling reaction of organozinc iodides derived from a-amino acids with aromatic bromides to give substituted phenyl-
alanine derivatives is described, using either Pd(OAc)2 or Pd2(dba)3 in combination with P(o-Tol)3 as catalyst in DMF at 50 ꢀC. Similar results
are obtained using Pd[PtBu3]2 as catalyst. The difference in reactivity displayed between aryl iodides and bromides (ArI>ArBr) has been utilised
in a short synthesis of an unsymmetrical, orthogonally protected para-phenylene bis-alanine derivative.
Ó 2007 Elsevier Ltd. All rights reserved.
2
1. Introduction
partner, using 2.5 mol % Pd2(dba)3 and 10 mol % P(o-Tol)3
in DMF at 1 M concentration at room temperature, although
much lower loadings of Pd are actually required.3
The palladium-catalysed Negishi cross-coupling reaction
between aromatic halides and a, b and g-amino acid-derived
organozinc iodides has been widely used to synthesise a variety
of non-proteinogenic amino acid derivatives.1 In the course of
our investigations, it was found that organozinc reagents de-
rived from a-amino acids possessed enhanced intramolecular
co-ordination compared to the b- and g-amino acid reagents,
resulting in increased stability and consequently decreased re-
activity (Fig. 1).1
Recently the synthesis of a highly potent and selective non-
peptidic tyrosine phosphatase inhibitor reported by Szczepan-
kiewicz et al. included a palladium-catalysed cross-coupling
reaction between the organozinc iodide 1a, generated from the
serine-derived iodide 2a, and the aromatic bromide 1-amino-
4-bromonaphthalene.4 This transformation was accomplished
using Pd(OAc)2 (5 mol %) and P(o-Tol)3 (20 mol %) at elevated
temperature (65 ꢀC, Scheme 1).
Thus cross-coupling reactions of a-amino acid-derived
organozinc reagents have generally been performed with
a more reactive aromatic iodide as the electrophilic coupling
NH2
BocHN
MeO2C
BocHN
MeO2C
i)
Zn*
I
ii)
1 equiv. ArBr
5 mol% Pd(OAc)2
20 mol% P(o-Tol)3
DMF, 65 °C
2a
3a, 55%
BocHN
OMe
HN
ZnI
Zn
MeO2C
O
t
Scheme 1. RZnI cross-coupling with 1-amino-4-bromonaphthalene.4
BuO
O
X
1a
X=I or Solvent
The use of aromatic bromides and chlorides as electrophilic
coupling partners is attractive due to their lower cost and wider
availability. They are less reactive towards oxidative addition
than the corresponding aromatic iodides,5 which is directly
related to their bond dissociation energies (D298(PhꢁX):
Cl¼408; Br¼346 and I¼281 kJ molꢁ1).6 The Negishi cross-
coupling reaction of organozinc halides and alkyl and aryl
Fig. 1. Intramolecular co-ordination.
* Corresponding authors. Tel.: þ44 114 222 9464; fax: þ44 114 222 9303.
E-mail address: r.f.w.jackson@shef.ac.uk (R.F.W. Jackson).
y
Present address: Department of Pharmacy and Pharmacology, University
of Bath, Bath BA2 7AY, UK.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.031

682
C.L. Oswald et al. / Tetrahedron 64 (2008) 681e687
electrophiles is very diverse,7e9 although relatively few exam-
ples exist of couplings between functionalised alkylzinc halides
and either aromatic bromides or chlorides. Selected examples of
functionalised alkylzinc reagents include esters,10e13 silyl
ethers,14 bicyclic systems15 and Boc-protected amines.16,17 Pre-
vious reports have shown that the serine-derived alkylzinc
reagent 1a can couple with bromopyridines, although these
are activated electrophiles whose reactivity may be further en-
hanced upon co-ordination with residual metal ions in solu-
tion.18,19 The reaction shown in Scheme 1 is the only example
of a palladium-catalysed cross-coupling reaction between an
unactivated aromatic bromide and a zinc reagent derived from
an a-amino acid.
In an effort to extend the Negishi cross-coupling reaction to
aromatic bromides and chlorides, alternative reagents and
methods have been reported. A tetradentate phosphine ligand
with PdCl[(C3H5)]2 has been successfully used to couple
unfunctionalised alkylzinc bromides with aryl bromides in
THF at 70 ꢀC.20 Cross-coupling with aromatic chlorides re-
quires more forcing conditions and has been reported with
simple alkylzinc chlorides by Dai and Fu using Pd[PtBu3]2,21
a complex originally prepared by Otsuka,22 and Kappe using
Pd2(dba)3 under microwave irradiation.23
The example reported by Szczepankiewicz et al. in Scheme
1 uses Pd(OAc)2, which is reduced in situ by PAr3 to generate
the catalytically active Pd(0) species required for cross-cou-
pling.24,25 Complex mixtures of potentially catalytically active
neutral and anionic Pd(0) species are generated,26e31 includ-
ing an acetate bridged cyclopalladated dinuclear palladium
complex.32 In addition, halide anions play a major role in ca-
talysis.31 Use of Pd2(dba)3 as the Pd-source is further compli-
cated by the fact that the dba ligand is not simply a spectator,
but may affect the rate of oxidative addition.33e35
We have therefore investigated the Negishi cross-coupling
reaction between the organozinc iodide 1a and aromatic
bromides using the reported conditions, Pd(OAc)2/P(o-Tol)3
(Method A)4 and our usual system Pd2(dba)3/P(o-Tol)3
(Method B).1 Given the encouraging reports of Dai and Fu,
a third palladium source Pd[PtBu3]2 (Method C)21 was also
investigated.
Table 1
Pd-catalysed cross-coupling of iodide 2a with PhBra
Entry
Temp (ꢀC)
Method A yield %
Method B yield %
1
2
3
a
25
50
75
40
60
51
39
58
66
Method A: 5 mol % Pd(OAc)2 and 10 mol % P(o-Tol)3. Method B:
2.5 mol % Pd2(dba)3 and 10 mol % P(o-Tol)3. Reactions conducted in DMF
for 16 h. Yields refer to isolated products after column chromatography.
Theyield of the cross-coupling reaction between zinc reagent
1a and 4-bromoanisole in DMF using Pd[PtBu3]2 (5 mol %) as
catalyst (Method C) at a range of temperatures gave modest
yields (25e31%), essentially independent of temperature.
Based on these initial results, further optimisation of
methods A and B was conducted at 50 ꢀC. The effect of
Pd:phosphine ratio was also examined in the Pd(OAc)2 and
Pd2(dba)3 systems and the results are shown in Table 2.
A phosphine-free Pd(OAc)2-catalysed Fukuyama cross-
coupling reaction was recently reported between an alkylzinc
iodide and a thiolactone.41 In the absence of any phosphine
ligand, no reaction occurred in the system described above
(entry 1, Table 2). The highest yields obtained with Pd(OAc)2
were achieved with a ratio of 1:2 (Pd:P(o-Tol)3, entry 3). Inter-
estingly, the yield decreased using a molar ratio of 1:4 Pd:P
(entry 5), the conditions reported by Szczepankiewicz et al.4
The Pd2(dba)3 system appeared largely insensitive to the
amount of phosphine, with consistent yields being obtained
with various Pd:phosphine ratios (entries 6e8).
Table 2
Effects of Pd:phosphine ratioa
Entry
Method
Pd:P(o-Tol)3 ratio
Yieldb
%
1
2
3
4
5
6
7
8
a
A: 5 mol % Pd(OAc)2
1:0
1:1
1:2
1:3
1:4
1:1
1:2
1:4
NORc
45
60
53
46
58
B: 2.5 mol % Pd2(dba)3
58
53
Reactions conducted with organozinc iodide 1a and 1.3 equiv PhBr at
50 ꢀC in DMF for 16 h.
b
Yields refer to isolated products after column chromatography.
NORdno observable reaction.
2. Results and discussion
c
The serine-derived iodide 2a was prepared following liter-
ature procedures,36,37 and treated with zinc activated either
with chlorotrimethylsilane (TMSCl),38,39 or catalytic I2 fol-
lowing a procedure originally reported for insertion into alkyl
bromides.40 Initial results showed that PhBr could be coupled
with the organozinc reagent 1a with either Pd(OAc)2/P(o-Tol)3
(Method A) or Pd2(dba)3/P(o-Tol)3 (Method B) in modest
yields (Scheme 2 and Table 1).
Further optimisation studies showed that the reaction with
Pd(OAc)2 or Pd2(dba)3 (Method A or B) was complete after
2 h at 50 ꢀC and that the catalyst loading of Pd[PtBu3]2
(Method C) could be reduced from 5 mol % to 1.25 mol %,
with slightly improved yields. To investigate the substrate
scope and limitations of the reaction, a series of experiments
with various aryl bromides was conducted using the optimised
conditions. Due to the similar results obtained using both
Pd(OAc)2 and Pd2(dba)3, and the lower price of the former,
Pd(OAc)2 was chosen as the Pd-source (Method A). A number
of reactions were also conducted using Pd[PtBu3]2 (Method
C), for comparison. The results are shown in Table 3; see
also Scheme 2.
BocHN
MeO2C
BocHN
MeO2C
i)
Zn*
I
Ar
ii) ArBr, Pd/P source
DMF
2a
3
Scheme 2. Zinc insertion and Pd-catalysed cross-coupling.

C.L. Oswald et al. / Tetrahedron 64 (2008) 681e687
683
Table 3
Pd-catalysed cross-coupling of zinc reagent 1a with aryl bromides
Entry
ArBr
Product
Structure
BocHN
MeO2C
BocHN
MeO2C
Method Aa yield %
60
Method Ca yield %
54
ArI yieldb
%
1
PhBr
3b
64c
d
2
3
2-Naphthyl bromide
3c
34
47
46
NO2
BocHN
MeO2C
4-O2NeC6H4Br
3d
d
57c
OMe
BocHN
MeO2C
4
5
4-MeOeC6H4Br
3-MeOeC6H4Br
3e
3f
48
35
36
d
d
BocHN
MeO2C
d
OMe
MeO
BocHN
6
2-MeOeC6H4Br
4-FeC6H4Br
3g
3h
3i
13
40
23
43
44
20
d
d
d
d
d
42
33
36
57c
58c
59d
d
MeO2C
F
BocHN
MeO2C
7
OH
CHO
Me
BocHN
MeO2C
8
4-HOeC6H4Br
4-OHCeC6H4Br
4-MeeC6H4Br
BocHN
MeO2C
9
3j
BocHN
MeO2C
10
11
12
3k
3l
d
N
BocHN
MeO2C
5-Bromo-pyrimidine
4-EtO2CeC6H4Br
d
N
CO2Et
BocHN
MeO2C
3m
d
BocHN
MeO2C
13
9-Bromo-anthracene
3n
d
42
d
a
Method A: 5 mol % Pd(OAc)2, 10 mol % P(o-Tol)3, 2 h. Method C: 1.25 mol % Pd[PtBu3]2, 16 h. Reactions were conducted using ArBr (1.3 equiv) at 50 ꢀC in
DMF. Yields refer to isolated products after column chromatography, based on starting serine-derived iodide 2a.
b
Yield from the corresponding ArI, using Method B.
See Ref 42.
See Ref 43.
c
d
Pd-catalysed cross-coupling with bromobenzene gave mod-
est yields with both methods, comparable to that obtained with
PhI (entry 1, Table 3). Similar yields were obtained with the
electron poor 4-NO2 derivative and the electron rich 4-MeO
derivative (47% and 48% yield, respectively, Method A,
entries 3 and 4). The yield however did diminish with the
3-MeO substituent (35%, entry 5) dropping to 13% yield
with the 2-MeO derivative, presumably due to steric crowding,
although 57% yield was still achieved using 2-iodoanisole (en-
try 6). Unprotected phenols are tolerated in the Negishi cross-
coupling reaction with phenolic iodides (59%),43 however, the
slower rate of cross-coupling with aryl bromides results in
a much reduced yield (entry 8), although aldehydes were
shown to be compatible (entry 9). Using either Method A or

684
C.L. Oswald et al. / Tetrahedron 64 (2008) 681e687
C with 5-bromopyrimidine gave poor yields (20% and 33%,
respectively, entry 11), defining the scope of the process.
While the enantiomeric purity of the products was not explic-
itly determined, the lack of any detectable racemisation in all
previous work, combined with specific rotations of known
compounds in good agreement with the literature, suggests
that the compounds are enantiomerically pure.
3. Conclusions
From the initial reported example, the palladium-catalysed
Negishi cross-coupling reaction of a-amino acid-derived orga-
nozinc reagents has been extended to include a range of aro-
matic bromide electrophiles. The reaction proceeds with
various palladium sources at 50 ꢀC, although it is more suscep-
tible to the presence of acidic protons and to steric crowding
than coupling with the corresponding aromatic iodide.
The synthesis of the bis-alanine derivative 4 serves to demon-
strate the application of this methodology to the synthesis of
unsymmetrical, orthogonally protected and enantiomerically
pure phenylene bis-alanine derivatives. In addition, this flexible
approach could be used to incorporate a variety of a, b and/or
g-amino acids with various substituted aromatic cores.
2.1. Application
The difference in reactivity displayed between aromatic
iodides and bromides with a-amino acid-derived organozinc
reagents can be used to synthesise orthogonally protected, un-
symmetrical and enantiomerically pure phenylene bis-alanine
derivatives. Phenylene bis-amino acid derivatives have attracted
interest as structural variants of 2,6-diaminopimelic acid44,45
and related bis-amino acids, which are present in various
cyclic peptide antibiotics.46 A dilactoside derivative based on
m-phenylene bis-alanine was recently shown to inhibit selec-
tively galectin-1,47 a member of a family of proteins associated
with cancer.48 Phenylene bis-amino acid derivatives have also
been studied as mimics of a helix-turn-helix present in DNA-
binding proteins,49 supramolecular polymers50 and as asymmet-
ric catalysts.51
4. Experimental
4.1. General experimental
All moisture/air sensitive reactions were conducted under
a positive pressure of nitrogen in flame dried glassware. All re-
agents used were purchased from commercial sources without
further purification or prepared and purified according to liter-
ature procedure. Dry DMF was distilled from calcium hydride
Selected examples of previous syntheses include those us-
ing phase transfer catalysis,52e54 diastereoselective45,50,55e57
and non-selective58 alkylation, and catalytic asymmetric hy-
drogenation,59e61,49 which was applied to the synthesis of un-
symmetrical phenylene bis-a-amino acids. An unsymmetrical
orthogonally protected biphenyl derivative has been reported
using a Pd-catalysed SuzukieMiyaura cross-coupling reac-
tion, although the product was found to be racemic.54
Using the previously reported standard cross-coupling reac-
tion conditions for aromatic iodides,1,62 reaction of the orga-
nozinc reagent 2a with 1-bromo-4-iodobenzene, in the
presence of 2.5 mol % Pd2(dba)3 and 10 mol % P(o-Tol)3 at
room temperature, selectively gave the 4-bromo-phenylalanine
derivative 3o in 57% yield after column chromatography
(Scheme 3). Treatment of the aromatic bromide 3o with the
differentially protected serine-derived organozinc reagent
1b,63 in the presence of 5 mol % Pd(OAc)2 and 10 mol %
P(o-Tol)3 at 50 ꢀC for 2 h (Method A), gave the orthogonally
protected, unsymmetrical para-phenylene bis-alanine deriva-
tive 4 in 37% isolated yield.
˚
and stored over 4 A molecular sieves. Petroleum ether refers to
the fraction with a boiling point between 40e60 ꢀC. Thin layer
chromatography (TLC) was performed on precoated plates
(Merck aluminium sheets silica 60 F254, Art. no. 5554). Flash
column chromatography was performed on silica gel 60 (Merck
9385).
For known compounds, data is only included when litera-
ture values are either unavailable or, in the case of NMR
data, recorded at lower field strength. Nuclear Magnetic Res-
onance (NMR) spectra were recorded on a Bruker AMX2-
400 or a Bruker DRX-500 NMR spectrometer at room temper-
ature. Chemical shifts were measured relative to residual
solvent and are expressed in parts per million (d). Coupling
constants (J ) are given in hertz and are quoted to the nearest
0.5 Hz. High-resolution mass spectra were recorded using
a MicroMass LCT operating in electrospray (ES) mode or
a MicroMass Prospec operating in electro impact (EI) mode.
Chemical analyses were performed using a PerkineElmer
2400 CHN elemental analyser. Optical rotations were mea-
sured on a PerkineElmer 241 automatic polarimeter at l
589 nm (Na, D-line) with a path length of 1 dm at the stated
temperature and concentrations. The concentration is given
in g/100 mL and the optical rotations are quoted in
10ꢁ1 deg cm2 gꢁ1. Infrared spectra were recorded on a
PerkineElmer Paragon 100 FTIR spectrophotometer (nmax
in cmꢁ1) with KBr disks.
Br
i) Zn*
BocHN
MeO2C
BocHN
MeO2C
ii) 4-I-C6H4Br
I
Pd2(dba)3/P(o-Tol)3
2a
3o, 57%
ZHN
rt, DMF
t
iii)
CO2 Bu
ZnI
BocHN
MeO2C
t
BuO2C
1b
NHZ
4.1.1. General procedure for Negishi cross-coupling
reactions catalysed by Pd(OAc)2 or Pd2(dba)3 (Method
A or B)
A catalytic amount of iodine (typically 5e10 mg) was added
to a rapidly stirred suspension of zinc dust (392 mg, 6 mmol) in
Pd(OAc)2/P(o-Tol)3
4, 37%
50 °C, DMF
Scheme 3. Sequential Pd-catalysed cross-coupling. (i) Zn, cat. I2, DMF. (ii)
4-IeC6H4Br, 2.5 mol % Pd2(dba)3, 10 mol % P(o-Tol)3, rt, 16 h. (iii) 1b,
5 mol % Pd(OAc)2, 10 mol % P(o-Tol)3, 50 ꢀC, 2 h, DMF (Method A).

C.L. Oswald et al. / Tetrahedron 64 (2008) 681e687
685
DMF (1.0 mL) in a 25 mL one-necked round-bottomed flask fit-
ted with a 3-way tap with a magnetic stirrer bar. N-(tert-Butoxy-
carbonyl)-L-iodoalanine methyl ester 2a (329 mg, 1 mmol)
was then added in one portion to the rapidly stirred suspension
of now activated zinc in DMF and a slight exotherm was ob-
served. Thereaction mixturewas stirred for a further 5 min, until
the temperature had returned to room temperature. Stirring was
stopped and the zinc dust allowed to settle. The solution was re-
moved from the activated zinc via syringe and added to a sepa-
rate side-arm round bottom flask, containing the electrophile
(1.3 mmol), P(o-Tol)3 (30 mg, 0.1 mmol, 10 mol %) and either
Pd(OAc)2 (11 mg, 0.05 mmol, 5 mol %, Method A) or
Pd2(dba)3 (23 mg, 0.025 mmol, 2.5 mol %, Method B), and rap-
idly stirred for 2 h at 50 ꢀC under a nitrogen atmosphere. The
crude reactionmixturewas placed directly on a silica gel column
and purified by gradient column chromatography with petro-
leum ethereEtOAc.
4.1.2.3. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(40-nitro-
phenyl)propanoate (3d). By Method A, compound 3d was
isolated as a yellow/orange oil, and recrystallised from
Et2Oeheptane to yield a pale yellow solid (153 mg, 47%),
mp 100e101 ꢀC, lit. value42 95e97 ꢀC; m/z (EIþ) found Mþ
324.13123. C15H20N2O6 requires 324.13214. Spectroscopic
data consistent with that previously reported.42
4.1.2.4. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(40-meth-
oxyphenyl)propanoate (3e). By Method A (148 mg, 48%) and
Method C (83 mg, 36% yield), compound 3e was isolated as
a colourless oil. [a]D20 þ50.0 (c 1.8, CHCl3), lit.65 value
[a]2D0 þ59.2 (c 1.8, CHCl3); dH (500 MHz; CDCl3) 1.34 (9H,
t
s, CO2 Bu), 2.92 (1H, dd, J 14.0 and 5.5 Hz, CHAHBCHNH),
2.98 (1H, dd, J 14.0 and 6.0 Hz, CHAHBCHNH), 3.64 (3H, s,
CO2Me), 3.71 (3H, s, ArOMe) 4.44e4.48 (1H, m,
CH2CHNH), 4.89 (1H, br d, J 8.0 Hz, CH2CHNH ), 6.72
(2H, d, J 8.0 Hz, Ar) and 6.96 (2H, d, J 8.0 Hz, Ar); dC
(125 MHz; CDCl3) 27.3, 32.2, 51.2, 53.5, 54.2, 78.9, 113.0,
126.9, 129.3, 154.1, 157.7 and 171.4; m/z (ESþ) found MHþ
310.1655. C16H24NO5 requires 310.1654. Spectroscopic
data consistent with the 200 MHz 1H NMR previously
reported.65
4.1.2. General procedure for Negishi cross-coupling
reactions catalysed by Pd[tBu3]2 (Method C)
Chlorotrimethylsilane (6 mL) was added to a stirred suspen-
sion of zinc dust (294 mg, 4.5 mmol) in DMF (0.5 mL) in
a 25 mL one-necked round-bottomed flask fitted with a 3-
way tap. After 30 min the solvent was removed by syringe
and the zinc washed with 0.5 mL of DMF. The solvent was re-
moved again via syringe and the activated zinc dried under
vacuum. A solution of N-(tert-butoxycarbonyl)-L-iodoalanine
methyl ester 2a (247 mg, 0.75 mmol) in DMF (0.75 mL)
was added to the activated zinc and stirred. After 10e
15 min, TLC [petroleum ethereEtOAc (1:1)] showed com-
plete zinc insertion. The electrophile (1 mmol) followed by
Pd[PtBu3]2 (5 mg, 0.01 mmol, 1.25 mol %) was added and
the mixture stirred for 16 h at 50 ꢀC under nitrogen. The
resulting mixture was diluted with Et2O (50 mL) and washed
with saturated ammonium chloride solution (20 mL), brine
(20 mL) and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure and the residue purified by
column chromatography with dichloromethaneeEtOAc.
4.1.2.5. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(30-meth-
oxyphenyl)propanoate (3f). By Method A, compound 3f was
isolated as
a
pale orange oil (108 mg, 35%). [a]D22
þ24.7 (c 1.9, CHCl3); nmax/cmꢁ1 (KBr disk) 3368, 1746,
1715, 1608 and 1586; dC (125 MHz; CDCl3) 28.3, 38.3,
52.2, 54.3, 55.2, 79.9, 112.5, 115.0, 121.6, 129.6, 137.5,
155.1, 159.7 and 172.2; m/z (ESþ) found MHþ 310.1647.
C16H24NO5 requires 310.1654. Spectroscopic data consistent
with that previously reported.66
4.1.2.6. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(20-meth-
oxyphenyl)propanoate (3g). By Method A, compound 3g
was isolated as a pale orange oil (40 mg, 13%). [a]2D2 þ12.9
(c 0.68, CH2Cl2), lit.42 value [a]D20 þ14.9 (c 0.68, CH2Cl2); m/z
(EIþ) found Mþ 309.15719. C16H23NO5 requires 309.15762.
Spectroscopic data consistent with that previously reported.42
4.1.2.1. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-phenyl-
propanoate (3b). Using Method A, with 0.75 mmol of iodide
2a, compound 3b (129 mg, 60%) was isolated as a light yellow
oil. Method C gave 3b (112 mg, 54% yield). [a]2D2 þ41.8 (c 0.55,
CH2Cl2), lit. value42 [a]D20 þ46.9 (c 3.43, CH2Cl2); m/z (ESþ)
found MHþ 280.1548. C15H22NO4 requires 280.1549. Spectro-
scopic data consistent with that previously reported.42
4.1.2.7. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(40-fluo-
rophenyl)propanoate (3h). By Method A, compound 3h was
isolated as a pale yellow oil (119 mg, 40%). [a]2D1 þ44.1
(c 0.72, CH2Cl2), lit.42 value [a]D20 þ30.5 (c 0.1, CH2Cl2); m/z
(ESþ) found MHþ 298.1464. C15H21NO4F requires 298.1455.
Spectroscopic data consistent with that previously reported.42
4.1.2.2. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(2-naph-
thyl)propanoate (3c). Using Method A, with 0.75 mmol of
iodide 2a, compound 3c (85.5 mg, 34%) was isolated as a col-
ourless solid. Method C gave compound 3c (113 mg, 46%
yield). Mp 84e86 ꢀC, lit. value64 85e86 ꢀC; [a]2D1 þ58.3
(c 0.99, CH2Cl2), lit. value64 [a]D32 þ59.9 (c 2.62, CHCl3).
Anal. found C, 69.17; H, 7.12; N, 4.07. C19H23NO4 requires
C, 69.28; H, 7.04; N, 4.25%; m/z (ESþ) found MHþ
330.1702. C19H24NO4 requires 330.1705. Spectroscopic data
consistent with that previously reported.64
4.1.2.8. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(40-hy-
droxyphenyl)propanoate (3i). By Method A, compound 3i
was isolated as a pale yellow oil (67 mg, 23%). [a]2D1 þ53.1
(c 1.0, CHCl3), lit.67 value [a]D20 þ48.2 (c 1.0, CHCl3); m/z
(ESþ) found MHþ 296.1490. C15H22NO5 requires 296.1498.
Spectroscopic data consistent with that previously reported.68
4.1.2.9. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(40-for-
myl-phenyl)propanoate (3j). By Method A, compound 3j

686
C.L. Oswald et al. / Tetrahedron 64 (2008) 681e687
was isolated as an orange oil (132 mg, 43%). [a]2D3 þ43.4
(c 0.87, CHCl3), lit.69 value [a]D20 þ64.0 (c 2.0, CHCl3); m/z
(ESþ) found MNaþ 330.1310. C16H21NO5Na requires
330.1317. Spectroscopic data consistent with that previously
reported.69
was isolated as a yellow solid (119 mg, 42% yield). Mp
159.8e160.0 ꢀC; [a]D22 þ21.4 (c 2.24, CH2Cl2); nmax (KBr)/
cmꢁ1 3369, 2930, 1736, 1686, 1524, 1255 and 1164; dH
t
(500 MHz, CDCl3) 1.38 (9H, s, CO2 Bu), 3.30 (3H, s,
CO2Me), 4.00e4.06 (1H, m, CHAHBCHNH), 4.15 (1H, dd,
J 14.0 and 7.0 Hz, CHAHBCHNH), 4.75e4.80 (1H, m,
CHAHBCHNH), 5.31 (1H, d, J 7.5 Hz, CHAHBCHNH ), 7.47
(2H, t, J 7.5 Hz, Ar), 7.54 (2H, dt, J 8.5 and 1.0 Hz, Ar),
8.00 (2H, d, J 8.5 Hz, Ar), 8.31 (2H, d, J 8.5 Hz, Ar) and
8.38 (1H, s, Ar); dC (100 MHz, CDCl3) 28.2, 31.1, 52.1,
54.5, 79.8, 123.9, 124.8, 126.1, 127.0, 128.3, 129.2, 130.5,
131.3, 154.8 and 172.6. m/z (EI) 380 (MHþ, 8%), 324 (37),
280 (100), 263 (14) and 249 (4). Found MHþ 380.1867,
C23H26NO4 requires 380.1862.
4.1.2.10. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-p-tolyl-
propanoate (3k). By Method A (130 mg, 44%) and Method
C (92 mg, 42% yield), compound 3k was isolated as an
orange oil. [a]D21 þ46.0 (c 0.93, CHCl3), lit.70 value [a]2D4
þ52.1 (c 1.0, CHCl3); nmax/cmꢁ1 (KBr disk) 3370, 1747,
t
1716 and 1515; dH (500 MHz; CDCl3) 1.35 (9H, s, CO2 Bu),
2.24 (3H, s, ArMe) 2.94 (1H, dd, J 14.0 and 6.0 Hz,
CHAHBCHNH), 3.00 (1H, dd,
J
14.0 and 5.5 Hz,
CHAHBCHNH), 3.64 (3H, s, CO2Me), 4.45e4.50 (1H, m,
CH2CHNH), 4.89 (1H, br d, J 8.0 Hz, CH2CHNH ), 6.93
(2H, d, J 8.0 Hz, Ar) and 7.02 (2H, d, J 8.0 Hz, Ar); dC
(125 MHz; CDCl3) 21.1, 28.3, 37.9, 52.2, 54.5, 79.9, 129.2,
129.3, 132.8, 136.6, 155.1 and 172.4; m/z (EIþ) 293 (Mþ,
3%), 177 (24), 176 (100), 106 (24) and 105 (67). Found Mþ
293.16278. C16H23NO4 requires 293.16271. Spectroscopic
data consistent with the 250 MHz previously reported.70
4.1.2.14. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(40-bro-
mophenyl)propanoate (3o). By Method B using zinc dust
(432 mg, 6.6 mmol), N-(tert-butoxycarbonyl)-L-iodoalanine
methyl ester (362 mg, 1.1 mmol), 4-iodobromobenzene
(283 mg, 1 mmol), Pd2(dba)3 (23 mg, 2.5 mol %) and P(o-Tol)3
(30 mg, 10 mol %) in DMF (1.0 mL) for 16 h at room tem-
perature gave, after purification by column chromatography,
compound 3o as a yellow oil (204 mg, 57%). Rf [petro-
leum ethereEtOAc (8:2)] 0.33; [a]2D1 þ29.6 (c 1.35, CHCl3);
nmax/cmꢁ1 (KBr disk) 3372, 1746 and 1715; dH (500 MHz;
4.1.2.11. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(pyri-
midin-5-yl)propanoate (3l). By Method A (56 mg, 20%) and
Method C (69 mg, 33% yield), compound 3l was isolated as
a yellow oil. Rf [EtOAc] 0.34; [a]2D1 þ32.7 (c 1.26, CHCl3);
nmax/cmꢁ1 (KBr disk) 3248, 1745, 1712, 1563 and 1523; dH
t
CDCl3) 1.35 (9H, s, CO2 Bu), 2.92 (1H, dd, J 14.0 and
6.5 Hz, CHAHBCHNH), 3.02 (1H, dd, J 14.0 and 5.5 Hz,
CHAHBCHNH), 3.64 (3H, s, CO2Me), 4.47e4.51 (1H, m,
CH2CHNH), 4.91 (1H, br d, J 8.0 Hz, CH2CHNH ), 6.93
(2H, d, J 8.0 Hz, Ar) and 7.34 (2H, d, J 8.0 Hz, Ar); m/z
(ESþ) 380 (MNaþ, 5%), 358 (MHþ, 8), 304 (32), 302 (35),
260 (90) and 258 (100). Found MHþ 358.0660, C15H21NO4Br
t
(500 MHz; CDCl3) 1.35 (9H, s, CO2 Bu), 2.96 (1H, dd,
J 14.0 and 5.0 Hz, CHAHBCHNH), 3.15 (1H, dd, J 14.0 and
7.0 Hz, CHAHBCHNH), 3.69 (3H, s, CO2Me), 4.53e4.58
(1H, m, CH2CHNH), 5.12 (1H, br d, J 8.0 Hz, CH2CHNH ),
8.48 (2H, s, Ar) and 9.05 (1H, s, Ar); dC (125 MHz; CDCl3)
27.2, 32.2, 51.7, 52.8, 79.5, 128.9, 153.9, 156.5, 156.6 and
170.2; m/z (EIþ) 281 (Mþ, 4%), 94 (27), 85 (78), 83 (100)
and 57 (39). Found Mþ 281.13703, C13H19N3O4 requires
281.13756.
1
requires 358.0654. Spectroscopic data consistent with the H
NMR previously reported.71
4.1.2.15. 1-{(2S )-2-[(Benzyloxycarbonyl)amino]-2-[(tert-but-
oxycarbonyl)]ethyl}-4-{(2S )-2-[(tert-butoxycarbonyl)amino]-
2-(methoxycarbonyl)ethyl}-benzene (4). By Method A using
zinc dust (176 mg, 2.7 mmol), N-(benzyloxycarbonyl)-
L-iodoalanine tert-butyl ester63 (162 mg, 0.40 mmol), aryl
bromide 3o (134 mg, 0.375 mmol), Pd(OAc)2 (4.2 mg,
0.0187 mmol), P(o-Tol)3 (11 mg, 0.0361 mmol) in DMF
(1.0 mL) for 2 h at 50 ꢀC gave, after purification by column
chromatography, compound 4 as a yellow/orange oil (78 mg,
37%). Rf [petroleum ethereEtOAc (8:2)] 0.17; [a]2D1 þ53
(c 1.4, CH2Cl2); nmax/cmꢁ1 (KBr disk) 3347, 1716 and 1505;
4.1.2.12. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(40-
ethoxycarbonylphenyl)propanoate (3m). By Method C, com-
pound 3m was isolated as a pale yellow oil (95 mg, 36%
yield). [a]D22 þ51.3 (c 1.00, CH2Cl2); nmax (liquid film)/cmꢁ1
3347, 2986, 1737, 1714, 1687 and 1609; dH (400 MHz,
t
CDCl3) 1.37 (3H, t, J 7.0 Hz, CH2CH3), 1.40 (9H, s, CO2 Bu),
3.08 (1H, dd, J 13.5 and 5.5 Hz, CHAHBCHNH), 3.18 (H,
dd, J 13.5 and 5.5 Hz, CHAHBCHNH), 3.70 (3H, s, CO2Me),
4.35 (2H, q, J 7.0 Hz, CH2CH3), 4.58e4.62 (1H, m,
CHAHBCHNH), 5.00 (1H, d, J 7.5 Hz, CHAHBCHNH ), 7.19
(2H, d, J 8.0 Hz, Ar) and 7.96 (2H, d, J 8.0 Hz, Ar); dC
(100 MHz, CDCl3) 14.3, 28.2, 38.3, 52.3, 54.2, 60.9, 80.0,
129.3, 129.7, 130.2, 141.3, 157.8, 166.4 and 171.9; m/z (EI)
352 (MHþ, 100%), 296 (60) and 137 (86). Anal. found C,
61.31; H, 7.04; N, 3.73%. C18H25NO6 requires C, 61.52; H,
7.17; N, 3.99%.
t
dH (500 MHz; CDCl3) 1.31 (9H, s, CO2 Bu), 1.34 (9H, s,
t
CO2 Bu), 2.92e3.02 (4H, m, 2ꢂCH2CHNH), 3.61 (3H, s,
CO2Me), 4.41e4.98 (2H, m, 2ꢂCH2CHNH), 4.88 (1H, br d,
J 8.0 Hz, NHCO2), 5.02 (2H, s, NHCO2CH2Ph), 5.17 (1H,
d, J 7.5 Hz, NHCO2) 6.95 (2H, d, J 7.5 Hz, Ar), 7.00 (2H,
d, J 7.5 Hz, Ar) and 7.22e7.29 (5H, m, CH2Ph); dC
(125 MHz; CDCl3) 28.0, 28.3, 37.9, 38.1, 52.2, 54.4, 55.2,
68.9, 79.9, 82.3, 128.1, 128.2, 128.5, 129.3, 129.7, 134.7,
134.9, 133.7, 155.1, 155.6, 170.5 and 172.3; m/z (ESþ) 557
(MHþ, 22%), 304 (50) and 302 (54). Found MHþ 557.2868,
C30H41N2O8 requires 557.2863.
4.1.2.13. Methyl 2-(S )-((tert-butoxycarbonyl)amino)-3-(an-
thracen-9-yl)propanoate (3n). By Method C, compound 3n

C.L. Oswald et al. / Tetrahedron 64 (2008) 681e687
687
30. Kozuch, S.; Shaik, S.; Jutand, A.; Amatore, C. Chem.dEur. J. 2004, 10,
3072e3080.
Acknowledgements
31. Kozuch, S.; Amatore, C.; Jutand, A.; Shaik, S. Organometallics 2005, 24,
2319e2330.
We thank Medivir (UK) for funding of a studentship
(T.C-M), and Drs U. Grabowska, A. Rae and M. J. Tozer for
their advice. We also thank the reviewers for their suggestions.
32. Dunina, V. V.; Gorunova, O. N. Russ. Chem. Rev. 2004, 73, 309e350.
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