Efficient synthesis of β- and γ-amino acid derivatives using new functionalised zinc reagents: Enhanced stability and reactivity of β-amido zinc reagents in dimethylformamide

Article abstract of DOI:10.1039/a707062d

The new zinc reagents 3 and 4 are not sufficiently stable to be prepared efficiently in THF, but they can be prepared in DMF under mild and convenient conditions; subsequent palladium- catalysed coupling with aromatic iodides gives protected β- and γ-amin

Full text of DOI:10.1039/a707062d

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Efficient synthesis of b- and g-amino acid derivatives using new functionalised
zinc reagents: enhanced stability and reactivity of b-amido zinc reagents in
dimethylformamide
Charles S. Dexter and Richard F. W. Jackson*
Department of Chemistry, Bedson Building, The University of Newcastle, Newcastle upon Tyne, UK NE1 7RU
The new zinc reagents 3 and 4 are not sufficiently stable to be
prepared efficiently in THF, but they can be prepared in
DMF under mild and convenient conditions; subsequent
palladium- catalysed coupling with aromatic iodides gives
protected b- and g-amino acids 11 and 12 in generally good
yields.
reagent), whilst coordination of the ester carbonyl was much
less pronounced (Table 1). We suggest that this lack of ester
coordination results in a relatively facile b-elimination of the
urethane group (promoted by the internal Lewis acid), since the
conformation required for elimination can be easily attained.
This stands in sharp contrast to the 13C NMR spectrum of the
serine-derived reagent 1 in [2H8]THF, which indicates that both
ester and urethane carbonyl groups are coordinated to zinc,
which in turn, we believe, is responsible for the significantly
greater stability of this reagent than the reagent 3 in THF. In
contrast to the situation in [2H8]THF, the 13C NMR spectrum of
3 in [2H7]DMF showed no significant changes in the shifts of
the two carbonyl carbon atoms on conversion of iodide 9 into
zinc reagent 3, which we interpret as indicating that there is no
coordination of either carbonyl group to zinc in this solvent. It
is interesting to note that in [2H7]DMF, the serine-derived zinc
reagent 1 preserves ester coordination (Table 1), indicating that
intramolecular co-ordination of an ester group which results in
a 5-membered ring is especially favourable. We therefore
explored the preparation of the zinc reagent 3 in dipolar aprotic
solvents, and were pleased that all solvents employed (DMF,
DMA, NMP and DMSO) were effective.12 In all the solvents,
preparation of the zinc reagent 3 and its subsequent coupling
with iodobenzene, to give 11a,‡ occurred at room temperature
in good yield. Given the convenience of using DMF,13
subsequent reactions were all carried out with this solvent, and
are summarised in Table 2 and Scheme 1. The only disappoint-
There has been increasing interest in the development of new
synthetic routes to b-amino acids, due to their importance as
components of natural products and modified peptides.1 The
asymmetric synthesis of b-amino acids has most often relied on
use of the chiral pool. For example, homologation of a-amino
acids,2 ring-opening of aziridine carboxylates3 and modifica-
tion of aspartic acid4–6 and asparagine7 have each been
explored. g-Amino acids have also been prepared using similar
strategies, for example by modification of glutamic acid4 and by
homologation of a-amino acids.8 A direct asymmetric synthesis
of aryl b- and g-amino acids has also been recently reported.9
In view of our development of other amino acid-derived zinc
reagents, such as the nucleophilic alanine equivalent 1 prepared
from protected iodoalanine 2,10 we have explored the potential
of the related reagents 3 and 4 for the synthesis of enantiomer-
ically pure b- and g-amino acids. The necessary iodide
precursors for the two reagents, 9 and 10, were prepared from
the protected aspartic and glutamic acid derivatives 5 and 6 by
standard methods.†
I
CO2Me
NHBoc
CO2Me
NHBoc
IZn
I
Table 1 13C NMR chemical shifts (d) of zinc reagents 1 and 3
R
2
THF
Ester
DMF
Ester
1
8a R = H
b
c
d
e
f
g
h
i
R = 2,3-(C=C)2
R = 4-Me
R = 2-MeO
R = 4-MeO
R = 2-NH2
R = 4-Br
Carbamate
Carbamate
HO2C
( )
( )
n CO2Me
n CO2Me
IZn
2
1
171.93
177.28
157.20
159.91
169.57
175.35
155.10
154.24
NHBoc
NHBoc
3 n = 1
4 n = 2
5 n = 1
6 n = 2
9
3
172.68
174.14
157.04
160.79
170.50
171.38
154.88
154.34
R = 2-F
R = 4-F
j
k
l
R = 2-NO2
R = 3-NO2
R = 4-NO2
CO2Me
Table 2 Preparation of b-amino acids
7
Yield
Aryl iodide
Product Ar
(%)a
Our initial efforts to prepare the zinc reagents 3 and 4, by
using zinc dust activated using the Knochel procedure in THF as
solvent,11 were disappointing. For example, formation and
coupling of the zinc reagent 3 with p-iodonitrobenzene 8l, under
the conditions previously developed for the zinc reagent 1, gave
the b-homophenylalanine derivative 11l in disappointing yield
(25%). Similar results were obtained using the zinc reagent 4.
1H NMR spectroscopy of the zinc reagent 3 prepared in
[2H8]THF indicated clearly that the main problem was
b-elimination of the urethane group to give the alkene 7.
Examination of the 13C NMR spectrum of the reagent 3 in
[2H8]THF indicated that there was significant coordination of
the urethane carbonyl group to zinc (implied by the downfield
shift of the urethane carbon atom upon formation of the zinc
8a Iodobenzene
8b 1-Iodonaphthalene
8c 4-Iodotoluene
8d 2-Iodoanisole
8e 4-Iodoanisole
11a
11b
11c
11d
11e
11f
11g
11h
11i
Ph
73
61
73
56
68
33
58
46
65
20
47
89
1-Naphthyl
4-MeC6H4
2-MeOC6H4
4-MeOC6H4
2-H2NC6H4
4-BrC6H4
2-FC6H4
8f 2-Iodoaniline
8g 4-Bromoiodobenzene
8h 2-Fluoroiodobenzene
8i 4-Fluoroiodobenzene
8j 2-Iodonitrobenzene
8k 3-Iodonitrobenzene
8l 4-Iodonitrobenzene
4-FC6H4
11j
11k
11l
2-O2NC6H4
3-O2NC6H4
4-O2NC6H4
a All yields are based on iodide 9.
Chem. Commun., 1998
75

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Footnotes and References
i, ii
nCO2Me
NHBoc
11 n = 1
12 n = 2
CO2Me
I
n
R
* E-mail: r.f.w.jackson@newcastle.ac.uk
NHBoc
† The aspartic and glutamic acid derivatives 5 and 6 were converted into the
corresponding N-hydroxysuccinimide esters (N-hydroxysuccinimide, N,NA-
dicyclohexylcarbodiimide) (ref. 14), reduced to the alcohols (NaBH4, H2O–
THF), and then converted into the iodides 9 and 10, respectively (PPh3, I2
imidazole, CH2Cl2) (ref. 15).
‡ The enantiomeric purity of 11a was determined by comparison of its
specific rotation, [[a]D +20.8 (c 1.28, MeOH)] with the literature value
[+19.9 (c 1.29, MeOH] (ref. 16). As an additional check, the ee of this
compound was determined as > 98% (by comparison with a racemic
sample) by capillary electrophoresis using a-cyclodextrin as chiral
selector.
9 n = 1
10 n = 2
Scheme 1 Reagents and conditions: i, Zn* (prepared from Zn dust using
1,2-dibromoethane, followed by Me3SiCl, in DMF), 15 min, room temp.; ii,
8 (1.33 equiv.), Pd2(dba)3 (2.5 mol%), P(o-MeC6H4)3 (10 mol%), room
temp., 3 h
Table 3 Preparation of g-amino acids
Yield
Aryl iodide
Product Ar
(%)a
1 For recent reviews, Enantioselective Synthesis of b-Amino Acids, ed. E.
Juaristi, Wiley-VCH, New York, 1996; D. C. Cole, Tetrahedron, 1994,
9517; G. Cardillo and C. Tomasini, Chem. Soc. Rev., 1996, 117.
2 For a recent example, see C. Guibourdenche, D. Seebach and F. Natt,
Helv. Chim. Acta, 1997, 80, 1.
3 J. E. Baldwin, R. M. Adlington, I. A. O’Neil, C. Schofield, A. C. Spivey
and J. Sweeney, J. Chem. Soc., Chem. Commun., 1989, 1852.
4 A. El Marini, M. L. Roumestant, P. Viallefont, D. Razafindramboa,
M. Bonato and M. Follet, Synthesis, 1992, 1104.
8a Iodobenzene
8c 4-Iodotoluene
8d 2-Iosoanisole
8e 4-Iodoanisole
8f 2-Iodoaniline
8h 2-Fluoroiodobenzene
8l 4-Iodonitrobenzene
12a
12c
12d
12e
12f
12h
12l
Ph
68
68
69
68
56
34
80
4-MeC6H4
2-MeOC6H4
4-MeOC6H4
2-H2NC6H4
2-FC6H4
4-O2NC6H4
5 C. W. Jefford and J. Wang, Tetrahedron Lett., 1993, 34, 1111.
6 J. M. Bland, Synth. Commun., 1995, 25, 467.
a All yields are based on iodide 10.
7 P. Gmeiner, Tetrahedron Lett., 1990, 31, 5717.
8 For example, see S. Hanessian and R. Schaum, Tetrahedron Lett., 1997,
38, 163.
ing yields occur with the use of ortho substituents, which appear
to be caused by steric problems, rather than by electronic ones.
The reasonable result obtained with 2-fluoroiodobenzene is in
sharp contrast to our previous complete failure to promote
coupling with this substrate.10
In an analogous way, the iodide 10 can be converted into the
zinc reagent 4, which then undergoes coupling with a range of
aromatic iodides in good yield to give a series of g-amino acids
12. These results are summarised in Table 3.
These results indicate that it is possible to prepare both b- and
g-amino acids using organozinc chemistry at room temperature
in a straightforward manner. Further applications of zinc
reagents 3 and 4, and of related zinc/copper reagents, to the
synthesis of other classes of b- and g-amino acid derivatives
will be reported in a future full paper.
We thank the EPSRC for a CASE award (C. S. D.) and for an
equipment grant (NMR spectrometer), Dr N. H. Rees for NMR
spectra, Merck Sharpe and Dohme, Terlings Park, for support,
the EU TMR programme (ERB-FMRX-CT96-0011), Dr J.
Elliott (MSD) for helpful discussions, L. Hitzel (MSD) for
chiral phase capillary electrophoresis and Dr S. Connolly, Astra
Charnwood, for experimental details of the preparation of
iodides 9 and 10. R. F. W. J. also thanks the Nuffield Foundation
for a One Year Science Research Fellowship.
9 Y. S. Park and P. Beak, J. Org. Chem., 1997, 62, 1574.
10 R. F. W. Jackson, N. Wishart, A. Wood, K. James and M. J. Wythes,
J. Org. Chem., 1992, 57, 3397; M. J. Dunn, R. F. W. Jackson,
J. Pietruszka and D. Turner, J. Org. Chem., 1995, 60, 2210.
11 P. Knochel and R. D. Singer, Chem. Rev., 1993, 93, 2117 and references
cited therein.
12 For previous work on the preparation of simple b-amido zinc reagents,
including an example in which a DMSO–THF mixture was found to be
preferable to THF alone, see R. Duddu, M. Eckhardt, M. Furlong,
H. P. Knoess, S. Berger and P. Knochel, Tetrahedron, 1994, 50,
2415.
13 For earlier examples of the use of DMF for palladium-catalysed cross-
coupling reactions of zinc reagents, see E.-i. Negishi, Z. R. Owczarczyk
and D. R. Swanson, Tetrahedron Lett., 1991, 32, 4453. For examples of
the use of dipolar aprotic solvents for the preparation of organozinc
reagents, see T. N. Majid and P. Knochel, Tetrahedron Lett., 1990, 31,
4413; C. Jubert and P. Knochel, J. Org. Chem., 1992, 57, 5425, and
references therein.
14 K. Shimamoto, M. Ishida, H. Shinozaki and Y. Ohfune, J. Org. Chem.,
1991, 56, 4167.
15 G. L. Lange and C. Gottardo, Synth. Commun., 1990, 20, 1473.
16 E. M. Gordon, J. D. Godfrey, N. G. Delaney, M. M. Assad, D. Von
Langen and D. W. Cushman, J. Med. Chem., 1988, 31, 2199.
Received in Liverpool, UK, 30th September 1997; 7/07062D
76
Chem. Commun., 1998