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J. Cianci et al. / Tetrahedron Letters 48 (2007) 5973–5975
enhanced reactivity3 did not improve the yield (Table 1,
entry 3). A significant decrease in yield was observed
when propylene oxide was used as an acid scavenger
in place of N,N-diisopropylethylamine (DIEA) (Table
1, entry 4).
Table 3. Isolated yields of dipeptides prepared under optimised
coupling conditions
Compound
Dipeptide
Yield (%)
3
Fmoc-Phe-NBn-Aib-OEt
Fmoc-Ile-NBn-Aib-OEt
Fmoc-Val-NBn-Aib-OEt
Fmoc-Pro-NBn-Aib-OEt
Fmoc-Phe-NMe-Aib-OEt
61
40
54
46
80
4
5
During the course of our research, Babu and co-workers
demonstrated coupling of a,a-disubstituted amino acids
using commercial zinc dust under microwave irradia-
tion, achieving high yields within short reaction times.12
Initial investigations of microwave-assisted, metal-med-
iated peptide coupling on our system showed promise,
but it was clear that optimisation was required to extend
the methodology to the synthesis of the extremely hin-
dered dipeptide 3.
6
718
there may be further scope for other metal-mediated
peptide couplings. Using zinc (5 equiv) at reflux for 6 h
without the microwave gave 67% conversion. Thus
bench-top peptide couplings with zinc are viable, but
they suffer from longer reaction times. As zinc is re-
ported to neutralise hydrochloride amino acid salts,2,13
it is conceivable that the zinc acts purely as a neutral
acid scavenger in these reactions, although whether zinc
has another role is still to be determined.
Using Fmoc-Phe-Cl and commercial zinc dust in dichlo-
romethane, (Table 2), the coupling conditions were
optimised by systematically varying temperature (entries
1–4), zinc concentration (entries 5–8) and reaction time
(entries 9–13). An excellent conversion to 3 (81% as
measured by LCMS) was achieved with the optimised
conditions: 5 equiv zinc for 2 h at 90 °C (entry 12). No
appreciable amount of premature deblocking of the
Fmoc group was observed over the course of the
reaction.
Using the optimised coupling conditions (Table 2, entry
12), dipeptide 3 was prepared and isolated in 61% yield
(Table 3), twice the best yield achieved with benchtop
reactions. The optimised conditions were applied to
the synthesis of other hindered dipeptides, incorporating
a-amino acid residues with branching at the b-position
(Table 3, compounds 4 and 5), and the structurally
constrained Pro residue (Table 3, compound 6). It is
noteworthy that the coupling proceeds cleanly and puri-
fication was considerably easier than when employing
the methods in Table 1. Application of the optimised
coupling conditions to the synthesis of a known dipep-
tide, Fmoc-Val-Aib-OBn,15,16 afforded a product with
matching optical rotation to the literature compound.
This suggests that racemisation does not occur during
the microwave reactions. Due to the prevalence of N-
methyl amino acids in natural products and biologically
relevant compounds,1,17 the synthesis of compound 7
(Table 3) was carried out and the dipeptide was isolated
in excellent yield.
The effect of the choice of metal and solvent on the reac-
tion was also investigated (Table 2). The degree of
conversion was reduced for both less polar (toluene,
entry 14) and more polar solvents (acetonitrile, entry
15) relative to dichloromethane. Furthermore, increas-
ing the temperature in acetonitrile to 150 °C led to a dra-
matic reduction in conversion to 3 (entry 16). Increase in
conversion to the dipeptide was not observed at temper-
atures above 90 °C in 1,2-dichloroethane (data not
shown). Although no increase in dipeptide formation
relative to zinc was observed with either magnesium
(entry 17) or iron (entry 18), reasonable conversion with
relatively clean reactions was afforded, indicating that
The synthesis of extremely hindered dipeptides employ-
ing commercial zinc dust under microwave irradiation
has been described. While the best conversion was
achieved with zinc, encouraging results were also ob-
served with iron and magnesium metals. The method
is free from racemisation and the products are easily
purified. This methodology could be applied to the syn-
thesis of various peptides containing N-alkyl- and/or
a,a-disubstituted amino acids.
Table 2. Optimisation of microwave reaction conditions for the
synthesis of 314
Entry Temperature
M
Time Solvent % Conversion
(°C)
(equiv) (min)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
40
60
80
90
90
90
90
90
90
90
90
90
90
90
90
150
90
90
Zn (2)
Zn (2)
Zn (2)
Zn (2)
Zn (0)
Zn (1)
Zn (5)
Zn (10)
Zn (5)
Zn (5)
Zn (5)
Zn (5)
Zn (5)
Zn (5)
Zn (5)
Zn (5)
60
60
60
60
60
60
60
60
10
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
11
22
25
41
38
42
60
56
50
60
60
81
82
Acknowledgements
We are grateful to the Australian National Health and
Medical Research Council and Bionomics Limited for
financial support. A.J.H. is a NHMRC Industry Fellow
(406698).
30
60
120
180
120
120
120
Toluene 59
MeCN
MeCN
DCM
DCM
66
25
36
47
Supplementary data
Mg (5) 120
Fe (5) 120
Detailed descriptions of experimental procedures are in-
cluded in the Supplementary data. Supplementary data