on. (entries 8 and 9, Table 2). Pyridyl groups however inhibit
the reaction (entry 7, Table 2). Secondary mercaptans show
a lower reactivity, which might in part be the consequence
of the increase in steric hindrance (entry 4, Table 2). Fur-
thermore, racemizations of the labile stereocenters, both in
the starting material as well as in the product, were not ob-
served. Despite the high reaction temperature no racemiza-
tion was observed (entry 8, Table 2).
We were pleased to find this method to be broadly appli-
cable to a variety of different carboxylic acid residues. Aro-
matic and aliphatic substrates are thioesterified in good to
excellent yields. Moreover, as observed for the thiol part, no
racemization of the starting materials or products was ob-
served during the reaction (entries 8–9, Table 3).
Having achieved the almost quantitative yield of tert-bu-
toxycarbonyl (Boc)-protected cystein (entry 8, Table 2) and
stereochemical integrity of the transesterification process
(entries 8–9, Table 3), we finally set out to test the reaction
in the addition of pronucleophiles to the thioester
(Scheme 1). As a proof-of-concept we chose to combine two
amino acid residues in a native chemical-ligation-type pro-
cess. Apart from the importance of this transformation in
chemical biology, it would support our concept of coopera-
tive iron–thiol catalysis. Indeed, whereas the combination of
N-Boc-protected phenylalanine aryl ester 19 and N-Boc-pro-
tected cystein methyl ester yielded the corresponding thio-
ester 30 in almost quantitative yield in excellent diastero-
meric ratio (reaction (1) Scheme 3), the “native chemical-li-
gation-type” peptide coupling was achieved upon employ-
ment of the unprotected cysteine as its hydrochlo-
Scheme 2.
ly the unsatisfying conversion rates reported in Table 1 re-
flect the thermodynamic equilibrium mixture between ox-
oester 1 and thioester 2.
After identifying the reason for the low conversion ob-
served in our initial studies, we tried to shift the equilibrium
towards the product side by employing the active p-chloro
aryl ester
(Table 2).
1 and the more electron-rich mercaptans
Fortunately, a wide range of mercaptans are acylated in
moderate to excellent yields. A variety of functional groups
are tolerated including acetals, carbamates, amides, and so
ride salt (reaction (2), Scheme 3). The desired
dipeptide 31 was obtained in good yield and with
Table 2. Scope of the thiol in the Fe-catalyzed thioesterification.[a]
high stereoisomeric purity. Running the reaction in
the absence of any catalyst under otherwise identi-
cal conditions did not lead to the formation of
either the thioester or the corresponding amide in
detectable amounts. To circumvent the solubility
Entry
Thiol
TBAFe
[mol%]
t
Product
Yield
[%][b]
problems, addition of tert-butanol as a co-solvent
proved necessary. Initial experiments to employ this
method to the synthesis of tripeptides were success-
ful, however these transformations required higher
catalyst concentrations (Scheme 3). Although ag-
gregation of both the starting material and product
became more problematic, the desired tripeptides
were obtained with almost perfect conservation of
enantiopurity.
U
[h]
1[c]
2
3
4
5
R=Bn
R=Ph
R=PhCH2CH2
R=iPr
R=CH3ACHTUNGTRENNUNG(CH2)15
2.5
5
2.5
2.5
2.5
6
3
4
5
6
7
95
65
88
46
80
24
24
24
24
6
5
24
8
94
7
5
48
9
–
In this communication we have reported the
iron-catalyzed synthesis of thioesters from stable p-
chloro aryl esters under neutral reaction conditions.
The transformation is applicable to a wide range of
different thiols and carboxylic acid residues. No iso-
merization of the labile stereocenters was observed.
With this catalysis in hand, an epimerization-free
native chemical-ligation-type peptide coupling was
developed that emphasizes the concept of using in-
situ-generated thio esters as reactive acyl donors in
the 1,2-addition of pronucleophiles to esters.
96
A
8
5
5
24
48
10
11
(ee=99%)[d]
9[e]
73
[a] All reactions were performed on a 0.5 mmol scale in dry 1,4-dioxane (0.5 mL) in
the presence of mol sieves 4 ꢂ at 808C. [b] Yields of the isolated product. [c] Thiol
(1.5 equiv). [d] Enantiomeric excess (ee) was determined by chiral HPLC. For details,
see the Supporting Information. [e] This reaction was performed on a 0.25 mmol scale,
with p-chloro aryl ester (2 equiv) and thiol (1 equiv).
8808
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8807 – 8809